Pyrazole compounds having therapeutic effect on multiple myeloma

ABSTRACT

Novel therapeutic agents for myeloma are provided. 
     A therapeutic agent for multiple myeloma containing a pyrazole compound represented by the formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1  is C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted with R 17 , C 1 -C 6  haloalkyl, phenyl, phenyl substituted with a R 11 &#39;s or the like, R 2  is a hydrogen atom, C 1 -C 6  alkyl, phenyl or phenyl optionally substituted with e R 21 &#39;s or the like, R 3  is a hydrogen atom or the like, X is a single bond or —(CR 6 , R 7 ) n —, each of R 4  and R 5  is independently C 1 -C 6  alkyl or the like, R 6  and R 7  are hydrogen atoms or C 1 -C 6  alkyl, R 8  is phenyl, phenyl optionally substituted with k R 81 &#39;s or the like, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.

TECHNICAL FIELD

The present invention relates to pyrazole compounds having growth inhibitory activity on multiple myeloma cells and therapeutic agents for myeloma using the compounds.

BACKGROUND ART

Multiple myeloma is a tumor resulting from malignant transformation of plasma cells, immunocytes in the bone marrow due to genetic abnormalities or the like. These malignant plasma cells (myeloma cells) migrate through the bloodstream and accumulate in the bone marrow where they proliferate, causing bone damage, hypercalcemia, renal failure, anemia, neuropathy and infections. Bone damage is caused by rapid proliferation of myeloma cells and resorption and breakdown of bones by osteoclasts stimulated by interleukin-6 (IL-6) which is released by myeloma cells. Bone damage can also cause the level of calcium in the bloodstream to rise, a condition called hyprecalcemia. Hypercalcemia injures the kidneys, resulting in reduced calcium excretion, increased urine production and the potential for dehydration. As myeloma cells crowd out normal cells in the bone marrow, the production of normal blood cells is also impaired. A reduction in leukocyte count can increase the high risk of infections due to immunodeficiency, and decreased erythrocyte counts can result in anemia. A reduction in platelets can prevent normal blood clotting. In addition, excess globulin and light chain proteins produced by myeloma cells can thicken the blood (hyperviscosity syndrome) and can cause circulatory problems in the kidneys. These proteins can also damage the kidneys and cause acute renal failure and chronic renal failure. Invasion of myeloma cells into the spinal canal can cause pain through spinal cord compression and can progress to paralysis. Accumulation of the amyloid protein derived from the M proteins secreted from myeloma cells can injure peripheral nerves (amyloidosis). Because multiple myeloma affects many tissues and organs in patients, the symptoms and signs are variable.

As mentioned above, multiple myeloma is a lethal disease associated with various complications, and there is no treatment that results in complete and permanent recovery from the disease with no or little side effect so fart. Therefore, there is a need for new treatment methods for multiple myeloma, and treatment of multiple myeloma with low molecular weight compounds having growth inhibitory effects on myeloma cells has been studied. However, no low molecular weight compounds having satisfying therapeutic effect on multiple myeloma have been found so far (Non-Patent Documents 1 to 5).

Meanwhile, pyrazole compounds are reported to have various biolactivities, and many pyrazole-based compounds have been developed for agricultural and medicinal use (Patent Document 1 and 2 and Non-Patent Documents 6 to 8).

PRIOR ART DOCUMENT Patent Documents

-   Patent Document 1: WO2001/085685 -   Patent Document 2: WO2008/073825

Non-Patent Documents

-   Non-Patent Document 1: Blood. 2008, vol. 111, p. 2516. -   Non-Patent Document 2 Hematology Am. Soc. Hematol. Educ. Program.     2009, p. 566 -   Non-Patent Document 3: Hematology Am. Soc. Hematol. Educ. Program.     2009, p. 578 -   Non-Patent Document 4: Blood. 2007, vol. 110, p. 3281. -   Non-Patent Document 5: Clin. Cancer Res. 2009, vol. 15, p. 5250. -   Non-Patent Document 6: J. Org. Chem. 1978, vol. 43, p. 808. -   Non-Patent Document 7: Chemische Berichte 1992, vol. 125, vol. 9, p.     2075 -   Non-Patent Document 8: Khimiya Geterotsiklicheskikh Soedinenii 1988,     vol. 5, p. 710

DISCLOSURE OF THE INVENTION Technical Problem

The object of the present invention is to solve the above-mentioned problems with prior art by providing pyrazole compounds and therapeutic agents using them against myeloma cells.

Solution to Problems

As a result of extensive studies on pyrazole compounds and inhibition of myeloma cell growth by them, the present inventors succeeded in synthesis of novel pyrazole compounds and found these compounds inhibit growth of myeloma cells. The present invention was accomplished on the basis of the discovery.

Namely, the present invention provides the following [1] to [10].

[1] A pyrazole compound represented by the formula (1):

[wherein R¹ is a hydrogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl substituted with a halogen atom, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynyl substituted with a halogen atom, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NR¹³, C(R¹²)═NOR¹³, D1 to D23, cyano, phenyl, phenyl substituted with a R¹¹'s, benzyl or benzyl having a benzene ring which may be substituted with a R¹¹'s, when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, and when there are two neighboring R¹¹'s, the two neighboring R¹¹'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R¹¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R² is a hydrogen atom, a halogen atom, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl substituted with a halogen atom, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynyl substituted with a halogen atom, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NR¹³, —C(R¹²)═NOR¹³, D1 to D23, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—, —OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkenyl optionally substituted with R³¹, C₂-C₆ alkynyl, C₂-C₆ alkynyl optionally substituted with R³¹, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴, benzyl or benzyl having a benzene ring which may be substituted with g R¹⁵'s, and when g is an integer of at least 2, each R¹⁵ may be identical with or different from one another, X is a single bond or —(CR⁶, R⁷)_(n)— each of R⁴ and R⁵ is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R⁴ and R⁵ may form —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂CH₂— to form a 3-membered, 4-membered, 5-membered or 6-membered ring together with the carbon atoms attached to R⁴ and R⁵, each of R⁶ and R⁷ is independently a hydrogen atom or C₁-C₆ alkyl, R⁸ is D1 to D23, E1 to E8, M1 to M9, C₃-C₁₀ cycloalkyl, F1, F2, C₃-C₁₀ cycloalkenyl, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—, —OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, D1 to D23 are aromatic heterocyclic rings represented by the following structural formulae, respectively,

E1 to E8 are saturated heterocyclic rings represented by the following structural formulae, respectively,

M1 to M9 are partially unsaturated aromatic heterocyclic rings represented by the following formulae, respectively,

F1 to F2 are rings represented by the following formulae, respectively,

R^(x) is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, —OR⁸², —C(O)R¹², —C(O)OR¹², phenyl, phenyl which may be substituted with d R¹⁵'s, benzyl or benzyl having a benzene ring which may be substituted with d R¹⁵'s, and when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another, R^(y) is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, phenyl, phenyl which may be substituted with d R¹⁵'s, benzyl or benzyl having a benzene ring which may be substituted with d R¹⁵'s, and when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another, R^(z) is a halogen atom, cyano, nitro, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s1, s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, and

when there are two neighboring R^(z)'s, the two neighboring R^(z)'s, may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂, —OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two neighboring R^(z)'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present,

R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkoxy, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, nitro, cyano or phenyl, each of R¹² and R¹³ is independently a hydrogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ halocycloalkyl, D1 to D23, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, and when there are two neighboring R¹⁴'s, the two neighboring R¹⁴'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R¹⁴'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R¹⁴ is a halogen atom, nitro, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, phenoxy or phenyl, R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkyl, C₃-C₆ halocycloalkoxy, nitro, cyano or phenyl, R¹⁶ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkoxy, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkoxy, nitro, cyano or phenyl, and when there are two neighboring R¹⁶'s, the two neighboring R¹⁶'s may form —OCH₂O— to form a 5-membered ring together with the carbon atoms to the two R¹⁶'s, R¹⁷ is —C(O)OR¹², phenyl or phenyl substituted with a R¹¹'s, and when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, R²¹ is a halogen atom, nitro, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, —OR²³, —C(O)R²⁴, —C(O)OR²⁴, —NR²⁴R²⁵, —C(O)NR²⁴R²⁵, —S(O)₂NR²⁴R²⁵, phenyl or phenyl which may be substituted with f R²²'s, and when f is an integer of at least 2, each R²² may be identical with or different from one other, and when there are two neighboring R²²'s, the two neighboring R²²'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R²²'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R²² is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkoxy, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkoxy, nitro, cyano or phenyl, R²³ is a hydrogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, phenyl, phenyl which may be substituted with f R²²'s, benzyl or benzyl having a benzene ring which may be substituted with f R²²'s, when f is an integer of at least 2, each R²² may be identical with different from one another, each of R²⁴ and R²⁵ is independently a hydrogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ halocycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, 1-phenethyl, 1-phenethyl having a benzene ring which may optionally be substituted with b R¹⁴'s, 2-phenethyl, 2-phenethyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, R³¹ is a halogen atom or phenyl, each of R³², R³³ and R³⁴ is independently C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, R⁸¹ is a halogen atom, nitro, cyano, —C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, —OR²³, —C(R⁸³)═NR⁸⁴, —C(R⁸³)═NOR⁸⁴, —C(O)R²⁴, —C(O)OR²⁴, S(O)cR²⁴, —OS(O)₂R²⁴, —NR²⁴R²⁵, C(O)NR²⁴R²⁵, —C(S)NH₂, —S(O)₂NR²⁴R²⁵, phenyl or phenyl which may be substituted with m R²²'s, and when m is an integer of at least 2, each R²²′ may be identical with or different from one another, R⁸² is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, phenyl, phenyl which may be substituted with d R¹⁵'s, benzyl or benzyl having a benzene ring which may be substituted with d R¹⁵'s, and when d is an integer of at least 2, each R¹⁵′ may be identical with or different from one another, each of R⁸³ and R⁸⁴ is independently a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl, phenyl which may be substituted with d R¹⁵'s, benzyl or benzyl having a benzene ring which may be substituted with d R¹⁵'s, and when d is an integer of at least 2, each R¹⁵′ may be identical with or different from one another, Z is a halogen atom, cyano, nitro, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, —C(O)NH₂, —C(S)NH₂, or —S(O)₂NH₂, a, b, d, e, f, g, k and m are integers of from 1 to 5, c is an integer of from 0 to 2, q1 is an integer of from 0 to 3, q2 is an integer of from 0 to 5, q3 is an integer of from 0 to 7, q4 is an integer of from 0 to 6, q5 is an integer of from 0 to 4, r is an integer of from 0 to 2, s1 is an integer of from 0 to 4, s2 is an integer of from 0 to 3, s3 is an integer of from 0 to 2, s4 is an integer of 0 or 1, n is an integer of 1, t is an integer of from 0 or 1, u is an integer of 0 or 1], a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [2] The pyrazole compound according to [1], wherein X is —(CR⁶R⁷)_(n)—, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [3] The pyrazole compound according to [2], wherein R¹ is C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NR¹³, —C(R¹²)═NOR¹³, D1 to D12, D18, D19, D21 to D23, phenyl or phenyl substituted with a R¹¹'s, and when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, when there are two neighboring R¹¹'s, the two neighboring R¹¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms optionally replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R² is a hydrogen atom, a halogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D1, D2, D4 to D12, D18, D19, D21 to D23, —C(O)R¹², —C(O)OR¹², benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴, benzyl or benzyl having a benzene ring which may be substituted with g R¹⁵'s, and when g is an integer of at least 2, each R¹⁵ may be identical with or different from one another, each of R⁴ and R⁵ is independently C₁-C₄ alkyl, each of R⁶ and R⁷ is a hydrogen atom, R⁸ is D1, D2, D4, D5, D7 to D12, D19, D22, D23, E1 to E8, F1, F2, C₃-C₁₀ cycloalkyl, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O—, —CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(x) is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl or phenyl, R^(y) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl or phenyl which may be substituted with d R¹⁵'s, and when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s1, s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, nitro or phenyl,

each of R¹² and R¹³ is independently a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ halocycloalkyl, D2, D4, D5, D7, D21, D22, D23, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, when there are two neighboring R¹⁴'s, the two neighboring R¹⁴'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹⁴'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present,

R¹⁴ is a halogen atom, nitro, cyano, —C₆ alkyl, C₁-C₆ haloalkyl, —C₆ alkoxy, C₁-C₆ haloalkoxy, phenoxy or phenyl, R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, R¹⁶ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, —C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy, and when there are two neighboring R¹⁶'s, the two neighboring R¹⁶'s may form —OCH₂O— to form a 5-membered ring together with the carbon atoms to the two R¹⁶'s, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, —C₁-C₁₀ alkoxy, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, nitro, cyano, phenoxy, phenyl or phenyl which may be substituted with f R²²'s, and when f is an integer of at least 2, each R²² may be identical with or different from one other, R²² is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy and when there are two neighboring R²²'s, the two neighboring R²²'s may form —OCH₂O— to form, together with the carbon atoms attached to the two R²²'s, a 5-membered ring each of R³², R³³ and R³⁴ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl, phenoxy, nitro or cyano, and Z is a halogen atom or C₁-C₆ alkyl, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [4] The pyrazole compound according to [3], wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)OR¹², D2, D4, D5, D7, D21 to D23, phenyl or phenyl substituted with a R¹¹'s, and when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, when there are two neigh R¹¹'s, the two neighboring R¹¹'s may form —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹'s, a 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R² is a hydrogen atom, a halogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D2, D7, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴ or benzyl, R⁸ is D2, D7, D23, F1, F2, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(y) is C₁-C₆ alkyl or phenyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s1, s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, each of R¹² and R¹³ is independently a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, R¹⁷ is —C(O)OR¹² or phenyl, R²² is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, each of R³², R³³ and R³⁴ is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl or phenoxy, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [5] The pyrazole compound according to [4], wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, phenyl or phenyl substituted with a R¹¹'s, and when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, R² is a hydrogen atom, a halogen atom, C₁-C₆ alkyl, D2, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, R⁸ is D2, F1, F2, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy or phenyl, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy or nitro, R¹² is C₁-C₆ alkyl, R¹⁷ is —C(O)OR¹² or phenyl, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₁-C₆ haloalkyl, nitro, cyano or phenyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, phenyl or phenoxy, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [6] The pyrazole compound according to [1], wherein R² is a hydrogen atom, a halogen atom, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₃-C₁₀ cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl substituted with a halogen atom, C₂-C₁₀ alkynyl, C₂-C₁₀alkynyl substituted with a halogen atom, —C(O)R¹², —C(O)OR¹², —C(R¹²)═NR¹³, —C(R¹²)═NOR¹³, D1 to D23, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—, —OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, X is a single bond, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [7] The pyrazole compound according to [6], wherein R¹ is C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NOR¹³, D1 to D12, D18, D19, D21 to D23, phenyl or phenyl substituted with a R¹¹'s, when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, and when there are two neighboring R¹¹'s, the two neighboring R¹¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R² is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D1, D2, D4 to D12, D18, D19, D21 to D23, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, and when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃ cycloalkyl, alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴, benzyl or benzyl having a benzene ring which may be substituted with g R¹⁵'s, and when g is an integer of at least 2, each R¹⁵ may be identical with or different from one another, each of R⁴ and R⁵ is independently C₁-C₄ alkyl, R⁸ is D1, D2, D4, D5, D7 to D12, D19, D22, D23, E1 to E9, F1, F2, C₃-C₁₀ cycloalkyl, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O—, —CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(x) is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl or phenyl, R^(y) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl or phenyl which may be substituted with d R¹⁵'s, benzyl or benzyl having a benzene ring which may be substituted with d R¹⁵'s, and when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s1, s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, nitro or phenyl, each of R¹² and R¹³ is independently a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₃-C₆ halocycloalkyl, D2, D4, D5, D7, D21, D22, D23, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, and when there are two neighboring R¹⁴'s, the two neighboring R¹⁴'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹⁴'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R¹⁴ is a halogen atom, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenoxy or phenyl, R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, R¹⁶ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy and when there are two neighboring R¹⁶'s, the two neighboring R¹⁶'s may form —OCH₂O— to form a 5-membered ring together with the carbon atoms to the two R¹⁶'s, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, nitro, cyano, phenoxy, phenyl or phenyl which may be substituted with f R²²'s, and when f is an integer of at least 2, each R²² may be identical with or different from one other, R²² is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy and when there are two neighboring R²²'s, the two neighboring R²²'s may form —OCH₂O— to form, together with the carbon atoms attached to the two R²²'s, a 5-membered ring, each of R³², R³³ and R³⁴ is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with b R¹⁴'s, phenyl or phenyl which may optionally be substituted with b R¹⁴'s, and when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl, phenoxy, nitro or cyano, and Z is a halogen atom or C₁-C₆ alkyl, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [8] The pyrazole compound according to [7], wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)OR¹², D2, D4, D5, D7, D21, D23, phenyl or substituted with a R¹¹'s, when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, and when there are two neighboring R¹¹'s, the two neighboring R¹¹'s may form —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R² is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D2, D7, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more

Z's which may be identical with or different from one another, if two or more Z's are present,

R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴ or benzyl,

R⁸ is D2, D7, D23, F1, F2, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and

when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present,

R^(y) is C₁-C₆ alkyl or phenyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, each of R¹² and R¹³ is independently hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ loalkyl or C₁-C₆ haloalkoxy, R¹⁷ is —C(O)OR¹² or phenyl, R²² is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, each of R³², R³³ and R³⁴ is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl or phenoxy, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [9] The pyrazole compound according to [8], wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, phenyl or phenyl substituted with a R¹¹'s, when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, R² is C₁-C₆ alkyl, D2, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl or phenyl optionally substituted with e R²¹'s, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, R⁸ is D2, F1, F2, phenyl or phenyl optionally substituted with k R⁸¹'s, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy or phenyl, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy or nitro, R¹² is C₁-C₆ alkyl, R¹⁷ is —C(O)OR¹² or phenyl, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₁-C₆ haloalkyl, nitro, cyano or phenyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy or phenoxy, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof. [10] A therapeutic agent for multiple myeloma containing the pyrazole compound as defined in any one of [1] to [9], a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

Advantageous Effects of Invention

The compounds of the present invention have growth inhibitory effect on multiple myeloma cells. Therefore, they are useful as therapeutic agents for multiple myeloma and can be used as preventive, therapeutic and improving agents for the disease.

DESCRIPTION OF EMBODIMENTS

Now, the present invention will be described in further detail.

The terms used herein are defined below.

The present invention is used when use of a compound having growth inhibitory action on myeloma cells is expected to improve pathological conditions. Multiple myeloma is a disease as a target of treatment with therapeutic agents containing the compounds of the present invention. Multiple myeloma is a tumor of plasma cells and can be staged by using the international staging system (ISS): stage I: serum β2 microglobulin<3.5 mg/L and serum albumin≧3.5 g/dL, stage II neither stage I nor III, stage III: serum β2 microglobulin≧5.5 mg.L.

Multiple myeloma is also classified as asymptomatic or symptomatic. Asymptomatic myeloma patients meet the criteria for myeloma with high levels of M proteins and a myeloma cell proportion in the bone marrow of 10% or more, but do not show no related tissue or organ impairment or symptoms. Asymptomatic myeloma includes smoldering multiple myeloma, indolent multiple myeloma and stage I multiple myeloma. Multiple myeloma is symptomatic if there is any of the associated organ or tissue disorders such as hypercalcemia, renal dysfunction, anemia, infections, hyperviscosity syndrome, amyloidosis and bone lesions. Other diseases classified as associated with multiple myeloma include nonsecretory myeloma characterized by no detection of M proteins in blood or urine, plasmacytoma accompanied by formation of a single lesion in a bone, extramedullary plasmacytoma defined as a cancer formed outside the bone marrow by myeloma cells and plasmacytic leukemia characterized by the presence of a detectable amount of plasma cells in peripheral blood.

Multiple myeloma is also therapeutically categorized as follows.

Responsive type: refers to myeloma which is responding to therapy. There has been a decrease in M proteins of at least 50%.

Stable type: refers to myeloma which has not responded to treatment (i.e., the decrease in M proteins has not reached 50%) but has not recognizably progressed.

Progressive type: refers to active myeloma which is worsening (i.e., increasing M proteins and worsening organ or tissue impairment).

Relapsed type: refers to myeloma which initially responded to treatment but has then begun to progress again. Patients may be further classified as having relapsed after initial therapy or after subsequent therapy.

Refractory type: refers to myeloma which has not responded to initial therapy, as well as relapsed myeloma which does not respond to subsequent treatment.

The multiple myeloma to be treated with the compounds of the present invention can be in any stages, in any classes, with any associated diseases, in any categories or in any disease statuses as described above.

A compound of the present invention can be used alone or in combination with at least one other therapeutic agent to ease at least one symptoms of multiple myeloma. A compound of the present invention may be administered at the same time as or prior to or subsequent to administration of the other therapeutic agent. A compound of the present invention may be administered through the same or different administration route as the other therapeutic agent. Such a therapeutic agent may be a chemotherapeutic agent, a supportive therapeutic agent or a combinations thereof.

As used herein, a chemotherapeutic agent is a substance which inhibits growth of cancer cells, such as bortezomib (Velcade (registered trademark)), melphalan, Predisone, vincristine, carmustine, cyclophosphamide, dexamethasone, thalidomide, doxorubicin, cicplatin, etoposide, cytarabine, but it is not restricted thereto.

A “supportive therapeutic agent” is an active substance which reduces the symptoms and complications of multiple myeloma. Examples of supportive therapeutic agent include antibiotics, bisphosphonates, blood cell growth factors, diuretics and analgesics.

Examples of antibiotics include sulfa drugs, penicillin, Phenethicillin, Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Nafcillin, Ampicillin, Amoxicillin, Cyclacillin, Carbenicillin, Ticarcillin, Piperacillin, Azlocillin, Mezlocillin, Mecillinam, Amdinocillin, Cephalosporin and derivatives thereof, Oxolinic acid, Amifloxacin, Temafloxacin, Nalidixic acid, Piromidic acid, Ciprofloxacin, Cinoxacin, Norfloxacin, Perfloxacin, Rosaxacin, Ofloxacin, Enoxacin, Pipemidic acid, Sulbactam, Clavulinic acid, β-Bromopenicillanic acid, β-Chloropenicillanic acid, 6-Acetylmethylenepenicillanic acid, Cephoxazole, Sultampicillin, Formaldehyde Hudrate Ester of Adinocillin and Sulbactam, Tazobactam, Aztreonam, Sulfazethin, Isosulfazethin, Norcardicins, m-Carboxyphenyl Phenylacetamidomethylphosphonate, Chlortetracycline, Oxytetracyline, Tetracycline, Demeclocycline, Doxycycline, Methacycline and Minocycline.

Examples of bisphosphonates include etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva).

Examples of diuretics include thiazide derivatives such as amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.

Examples of blood cell growth factors include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), erythropoietin, thrombopoietin, Oncostatin M and various interleukins.

Examples of analgesics include an opioid, a COX-2 inhibitor (e.g., Rofecoxib, Valdecoxib and Celecoxib), salicylates (e.g., ASPIRIN, choline magnesium trisalicylate, salsalate, dirunisal and sodium salicylate), propionic acid derivatives (e.g., fenoprofen calcium, ibuprofen, ketoprofen, naproxen and naproxen sodium), indoleacetic acid derivatives (e.g., indomethacin, sulfindac, etodalac and tolmetin), fenamates (e.g., mefenamic acid and meclofenamate), benzothiazine derivatives or oxicams (e.g., mobic or piroxicam) and pyrrolacetic acid (e.g., ketorolac).

As used herein “treating” includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease; ameliorating or improving a clinical symptom or indicator associated with the disease; or delaying, inhibiting or preventing the progression or onset of the disease.

A “subject” as the target of treatment with a compound of the present invention is a mammal, preferably a human, but can also be a pet animal (such as a dog or a cat) or a farm animal (such as a cow, a sheep, a pig or a horse).

The therapeutic agents containing the compounds of the present invention as an active ingredient may usually be administered as oral medicines such as tablets, capsules, powder, granules, pills and syrup, as rectal medicines, percutaneous medicines or injections. The agents of the present invention may be administered as a single therapeutic agent or as a mixture with other therapeutic agents. Though they may be administered as they are, they are usually administered in the form of medical compositions. These pharmaceutical preparations can be obtained by adding pharmacologically and pharmaceutically acceptable additives by conventional methods. Namely, for oral medicines, ordinary additives such as excipients, lubricants, binders, disintegrants, humectants, plasticizers and coating agents may be used. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be supplied as dry syrups to be mixed with water or other appropriate solvents before use. Such liquid preparations may contain ordinary additives such as suspending agents, perfumes, diluents and emulsifiers. In the case of rectal administration, they may be administered as suppositories. Suppositories may use an appropriate substance such as cacao butter, laurin tallow, Macrogol, glycerogelatin, Witepsol, sodium stearate and mixtures thereof as the base and may, if necessary, contain an emulsifier, a suspending agent, a preservative and the like. For injections, pharmaceutical ingredients such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol and other solvents or solubilizing agents, a pH regulator, an isotonizing agent and a stabilizer may be used to form aqueous dosage forms or dosage forms which need dissolution before use.

The dose of the therapeutic agents containing the compounds of the present invention for administration to human is usually about from 0.1 to 1000 mg/human/day in the case of oral drugs or rectal administration and about from 0.05 mg to 500 mg/human/day in the case of injections, though it depends on the symptoms of the patient. The above-mentioned ranges are mere examples, and the dose should be determined from the conditions of the patient.

When R³ is a hydrogen atom, the compounds of the present invention represented by the formula (1) can have tautomers (2) to (4) which undergo endocyclic or exocyclic isomerization, and the present invention covers these tautomers (2) to (4) and mixtures containing them in any ratios.

When the compounds of the present invention have an asymmetric center, whether or not resulting from an isomerization, the present invention covers both resolved optical isomers and mixtures containing them in any ratios.

The compounds of the present invention can have geometrical isomers such as E-isomers and Z-isomers, whether or not resulting from an isomerization, depending on the substituents, and the present invention covers both these geometrical isomers and mixtures containing hem in any ratios.

The compounds of the present invention represented by the formula (1) may be converted to pharmaceutically acceptable salts or may be liberated from the resulting salts, if necessary. Some of the compounds of the present invention can be converted, by ordinary methods, to acid addition salts with hydrogen halides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydriodic acid, with inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, chloric acid and perchloric acid, with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesuflonic acid, benzenesulfonic acid and p-toluenesulfonic acid, with carboxylic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid, with amino acids such as glutamic acid asparatic acid.

Some of the compounds of the present invention can be converted, by ordinary methods, to metal salts with alkali metals suchas lithium sodium and potassium, with alkaline earth metals such as calcium, barium and magnesium, with metals suchas aluminum zinc and copper.

The compounds of the present invention represented by the formula (1) or pharmaceutically acceptable salts thereof may be in the form of arbitrary crystals or arbitrary hydrates, depending on the production conditions. The present invention covers these crystals, hydrates and mixtures. They may be in the form of solvates with organic solvents such as acetone, ethanol and tetrahydrofuran, and the present invention covers any of these forms.

The compounds which serve as prodrugs are derivatives of the present invention having chemically or metabolically degradable groups which give pharmacologically active compounds of the present invention upon solvolysis or under physiological conditions in vivo. Methods for selecting or producing appropriate prodrugs are disclosed, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985). In the present invention, when the compound has a hydroxy group, acyloxy derivatives obtained by reacting the compound with appropriate acyl halides or appropriate acid anhydrides may, for example, be mentioned as prodrugs. Acyloxys particularly preferred as prodrugs include —OCOC₂H₅, —OCO(t-Bu), —OCOC₁₅H₃₁, —OCO(m-CO₂Na—Ph), —OCOCH₂CH₂CO₂Na, —OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂ and the like. When the compound of the present invention has an amino group, amide derivatives obtained by reacting the compound having an amino group with appropriate acid halides or appropriate mixed acid anhydrides may, for example, be mentioned as prodrugs. Amides particularly preferred as prodrugs include —NHCO(CH₂)₂₀OCH₃, —NHCOCH(NH₂)CH₃ and the like.

Next, specific examples of each substituent used herein will be given below. “n” denotes normal, “i” denotes iso, “s” denotes secondary, “t” or “tert” denotes tertiary, and “Ph” denotes phenyl.

As a halogen atom in the compounds of the present invention, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be mentioned. Herein, the expression “halo” also means such a halogen atom.

The expression C_(α)-C_(β) alkyl herein means a linear or branched hydrocarbon group containing from α to β carbon atoms such as a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1,1-dimethylbutyl group, a 1,3-dimethylbutyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group or a dodecyl group, and those within the designated carbon number range are selected.

The expression C_(α)-C_(β) haloalkyl herein means a linear or branched hydrocarbon group containing from a to β carbon atoms in which hydrogen atom(s) on carbon atom(s) are optionally substituted with halogen atom(s) which may be identical with or different from one another if two or more halogen atoms are present, such as a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a chlorofluoromethyl group, a dichloromethyl group, a bromofluoromethyl group, a trifluoromethyl group, a chlorodifluoromethyl group, a dichlorofluoromethyl group, a trichloromethyl group, a bromodifluoromethyl group, a bromochlorofluoromethyl group, a difluoroiodomethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2,2-difluoroethyl group, a 2-chloro2-fluoroethyl group, a 2,2-dichloroethyl group, a 2-bromo2-fluoroethyl group, a 2,2,2-trifluoroethyl group, a 2-chloro-2,2-difluoroethyl group, a 2,2-dichloro2-fluoroethyl group, a 2,2,2-trichloroethyl group, a 2-bromo-2,2-difluoroethyl group, a 1,1,2,2-tetrafluoroethyl group, a pentafluoroethyl group, a 1-chloro-1,2,2,2-tetrafluoroethyl group, a 2-chloro-1,1,2,2-tetrafluoroethyl group, a 1,2-dichloro-1,2,2-trifluoroethyl group, a 1-bromo-1,2,2,2-tetrafluoroethyl group, a 2-bromo-1,1,2,2-tetrafluoroethyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2,3-dichloropropyl group, a 3,3,3-trifluoropropyl group, a 3-bromo-3,3-difluoropropyl group, 2,2,3,3-tetrafluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a 1,1,2,3,3,3-hexafluoropropyl group, a heptafluoropropyl group, a 2,3-dichloro-1,1,2,3,3-pentafluoropropyl group, a 2-fluorol-methylethyl group, a 2-chlorol-methylethyl group, a 2-bromo-1-methylethyl group, a 2,2,2-trifluoro1-(trifluoromethyl)ethyl group, a 1,2,2,2-tetrafluoro1-(trifluoromethyl)ethyl group or a nonafluorobutyl group, and those within the designated carbon number range are selected.

The expression C_(α)-C_(β) cycloalkyl herein means a cyclic hydrocarbon group containing from a to β carbon atoms in the form of a 3- to 6-membered monocyclic or polycyclic ring which may optionally be substituted with an alkyl group as long as the number of carbon atoms does not exceed the designated carbon number range, such as a cyclopropyl group, a 1-methylcyclopropyl group, a 2-methylcyclopropyl group, a 2,2-dimethylcyclopropyl group, a 2,2,3,3-tetramethylcyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a bicyclo [2.2.1]heptan-2-yl group, a 1-adamantyl group or a 2-adamantyl group, and those within the designated carbon number range are selected.

The expression C_(α)-C_(β) halocycloalkyl means a cyclic hydrocarbon group containing from α to β carbon atoms in the form of a 3- to 6-membered monocyclic or complex ring which may optionally be substituted with an alkyl group as long as the number of carbon atoms does not exceed the designated carbon number range, in which hydrogen atom(s) on carbon atom(s) in a ring moiety and/or in a side chain are optionally substituted with halogen atom(s) which may be identical with or different from one another if two or more halogen atoms are present, such as a 2-fluorocyclopropyl group, a 2-chlorocyclopropyl group, a 2,2-difluorocyclopropyl group, a 2,2-dichlorocyclopropyl group, a 2,2-dibromocyclopropyl group, a 2,2-difluorol-methylcyclopropyl group, a 2,2-dichloro1-methylcyclopropyl group, a 2,2,3,3-tetrafluorocyclobutyl group or a 2-chloro-2,3,3-trifluorocyclobutyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkenyl herein means a linear or branched unsaturated hydrocarbon group containing from α to β carbon atoms and having one or more double bonds in the molecule such as a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-methylethenyl group, a butenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a 2-pentenyl group, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 2-ethyl2-propenyl group, a 1,1-dimethyl-2-propenyl group, a 2-hexenyl group, a 2-methyl-2-pentenyl group, a 2,4-dimethyl-2,6-heptadienyl group or a 3,7-dimethyl-2,6-octadienyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkynyl herein means a linear or branched unsaturated hydrocarbon group containing from a to β carbon atoms and having one or more triple bonds in the molecule such as an ethylene group, a 1-propynyl group, a 2-propynyl group, a 2-butynyl group, a 1-methyl-2-propynyl group, a 2-pentynyl group, a 1-methyl-2-butynyl group, a 1,1-dimethyl-2-propynyl group or a 2-hexynyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkoxy herein means an alkyl-O— group in which the alkyl is a previously mentioned alkyl group containing from a to βcarbon atoms, such as a methoxy group, an ethoxy group, a n-propyloxy group, an i-propyloxy group, a n-butyloxy group, an i-butyloxy group, a s-butyloxy group, a t-butyloxy group, a n-pentyloxy group, a n-hexyloxy group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkoxy herein means a haloalkyl-O— group in which the haloalkyl is a previously mentioned haloalkyl group containing from α to β carbon atoms, such as a difluoromethoxy group, a trifluoromethoxy group, a chlorodifluoromethoxy group, a bromodifluoromethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2,2,2-trifluoroethoxy group, a 1,1,2,2,-tetrafluoroethoxy group, a 2-chloro-1,1,2-trifluoroethoxy group, a 2-bromo-1,1,2-trifluoroethoxy group, a pentafluoroethoxy group, a 2,2-dichloro-1,1,2-trifluoroethoxy group, a 2,2,2-trichloro1,1-difluoroethoxy group, a 2-bromo-1,1,2,2-tetrafluoroethoxy group, a 2,2,3,3-tetrafluoropropyloxy group, a 1,1,2,3,3,3-hexafluoropropyloxy group, a 2,2,2-trifluoro1-(trifluoromethyl)ethoxy group, a heptafluoropropyloxy group or a 2-bromo-1,1,2,3,3,3-hexafluoropropyloxy group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylthio herein means an alkyl-S— group in which the alkyl is a previously mentioned alkyl group containing from α to β carbon atoms, such as a methylthio group, an ethylthio group, a n-propylthio group, an i-propylthio group, a n-butylthio group, an i-butylthio group, a s-butylthio group, a t-butylthio group, a n-pentylthio group or a n-hexylthio group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkylthio herein means a haloalkyl-S— group in which the haloalkyl is a previously mentioned haloalkyl group containing from α to β carbon atoms, such as a difluoromethylthio group, a trifluoromethylthio group, a chlorodifluoroethylthio group, a bromodifluoroethylthio group, a 2,2,2-trifluoroethylthio group, a 1,1,2,2-tetrafluoroethylthio group, a 2-chloro-1,1,2-trifluoroethylthio group, a pentafluoroethylthio group, a 2-bromo-1,1,2,2-tetrafluoroethylthio group, a 1,1,2,3,3,3-hexafluoropropylthio group, a heptafluoropropylthio group, a 1,2,2,2-tetrafluoro1-(trifluoromethyl)ethylthio group or a nonafluorobutylthio group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylsulfinyl herein means an alkyl-S(O)— group in which the alkyl is a previously mentioned alkyl group containing from α to β carbon atoms, such as a methylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an i-propylsulfinyl group, a n-butylsulfinyl group, an i-butylsulfinyl group, a s-butylsulfinyl group or a t-butylsulfinyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkylsulfinyl herein means a haloalkyl-S(O)— group in which the haloalkyl is a previously mentioned haloalkyl group containing from α to β carbon atoms, such as a difluoromethylsulfinyl group, a trifluoromethylsulfinyl group, a chlorodifluoromethylsulfinyl group, a bromodifluoromethylsulfinyl group, a 2,2,2-trifluoroethylsulfinyl group, a 2-bromo-1,1,2,2-tetrafluoroethylsulfinyl group, a 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethylsulfinyl group or a nonafluorobutylsulfinyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylsulfonyl herein means an alkyl-SO₂— group in which the haloalkyl is a previously mentioned haloalkyl group containing from α to β carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an i-propylsulfonyl group, a n-butylsulfonyl group, an i-butylsulfonyl group, a s-butylsulfonyl group, a t-butylsulfonyl group, a n-pentylsulfonyl group or a n-hexylsulfonyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkylsulfonyl herein means a haloalkyl-SO₂— group in which the haloalkyl is a previously mentioned haloalkyl group containing from α to β carbon atoms, such as adifluoromethylsulfonyl group, a trifluoromethylsulfonyl group, a chlorodifluoromethylsulfonyl group, a bromodifluoromethylsulfonyl group, a 2,2,2-trifluoroethylsulfonyl group, a 1,1,2,2-tetrafluoroethylsulfonyl group, a 2-chloro-1,1,2-trifluoroethylsulfonyl group or a 2-bromo-1,1,2,2-tetrafluoroethylsulfonyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylamino herein means an amino group in which either hydrogen atom is replaced by a previously mentioned alkyl group containing from α to β carbon atoms, such as a methylamino group, an ethylamino group, a n-propylamino group, an i-propylamino group, a n-butylamino group, an i-butylamino group or a t-butylamino group, and those within the designated carbon atom range are selected.

The expression di(C_(α)-C_(β) alkyl)amino herein means an amino group in which both hydrogen atoms are replaced by previously mentioned alkyl groups containing from α to β carbon atoms which may be identical with or different from each other, such as a dimethylamino group, an ethyl(methyl)amino group, a diethylamino group, a n-propyl(methyl)amino group, an i-propyl(methyl)amino group, a di(n-propyl)amino group, a n-butyl(methyl)amino group, an i-butyl(methyl)amino group or a t-butyl(methyl)amino group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylimino herein means an alkyl-N═ group in which the alkyl means a previously mentioned alkyl group containing from α to β carbon atoms, such as a methylimino group, an ethylimino group, a n-propylimino group, an i-propylimino group, a n-butylimino group, an i-butylimino group, a s-butylimino group, a n-pentylimino group or a n-hexylimino group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkoxyimino herein means an alkoxy-N=group in which the alkoxy means a previously mentioned alkoxy group containing from α to β carbon atoms, such as a methoxyimino group, an ethoxyimino group, a n-propyloxyimino group, an i-propyloxyimino group, a n-butyloxyimino group, a n-pentyloxyimino group or a n-hexyloxyimino group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylcarbonyl herein means an alkyl-C(O)— group in which the alkyl means a previously mentioned alkyl group containing from α to β carbon atoms, such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a 2-methylbutanoyl group, a pivaloyl group, a hexanoyl group or a heptanoyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkylcarbonyl herein means a haloalkyl-C(O)— group in which the haloalkyl means a previously mentioned haloalkyl group containing from a to β carbon atoms, such as a fluoroacetyl group, a chloroacetyl group, a difluoroacetyl group, a dichloroacetyl group, a trifluoroacetyl group, a chlorodifluoroacetyl group, a bromodifluoroacetyl group, a trichloroacetyl group, a pentafluoropropionyl group, a heptafluorobutanoyl group or a 3-chloro-2,2-dimethylpropanoyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkoxycarbonyl herein means an alkyl-O—C(O)— group in which the alkyl means a previously mentioned alkoxy group containing from α to β carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a n-propyloxycarbonyl group, an i-propyloxycarbonyl group, a n-butoxycarbonyl group, an i-butoxycarbonyl group or a t-butoxycarbonyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkoxycarbonyl herein means a haloalkyl-O—C(O)-group in which the haloalkyl means a previously mentioned haloalkyl group containing from α to β carbon atoms, such as a 2-chloroethoxycarbonyl group, a 2,2-difluoroethoxycarbonyl group, a 2,2,2-trifluoroethoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylaminocarbonyl herein means a carbamoyl group in which either hydrogen atom is replaced by a previously mentioned alkyl group containing from α to β carbon atoms, such as a methylcarbamoyl group, an ethylcarbamoyl group, a n-propylcarbamoyl group, an i-propylcarbamoyl group, a n-butylcarbamoyl group, an i-butylcarbamoyl group, a s-butylcarbamoyl group or a t-butylcarbamoyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkylaminocarbonyl herein means a carbamoyl group in which either hydrogen atom is replaced by a previously mentioned haloalkyl group containing from α to β carbon atoms, such as a 2-fluoroethylcarbamoyl group, a 2-chloroethylcarbamoyl group, a 2,2-difluoroethylcarbamoyl group or a 2,2,2-trifluoroethylcarbamoyl group, and those within the designated carbon atom range are selected.

The expression di(C_(α)-C_(β) alkyl)aminocarbonyl herein means a carbamoyl group in which both hydrogen atoms are replaced by previously mentioned alkyl groups containing from α to β carbon atoms which may be identical with or different from each other, such as an N,N-dimethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, an N,N-diethylcarbamoyl group, an N,N-di-n-propylcarbamoyl group or an N,N-di-n-butylcarbamoyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylaminosulfonyl herein means a sulfamoyl group in which either hydrogen atom is replaced by a previously mentioned alkyl group containing from α to β carbon atoms, such as a methylsulfamoyl group, an ethylsulfamoyl group, a n-propylsulfamoyl group, an i-propylsulfamoyl group, a n-butylsulfamoyl group, an i-butylsulfamoyl group, a s-butylsulfamoyl group or a t-butylsulfamoyl group, and those within the designated carbon atom range are selected.

The expression di(C_(α)-C_(β) alkyl)aminosulfonyl herein means a sulfamoyl group in which both hydrogen atoms are replaced by previously mentioned alkyl groups containing from α to β carbon atoms which may be identical with or different from each other, such as an N,N-dimethylsulfamoyl group, an N-ethyl-N-methylsulfamoyl group, an N,N-diethylsulfamoyl group, an N,N-di-n-propylsulfamoyl group or an N,N-di-n-butylsulfamoyl group, and those within the designated carbon atom range are selected.

The expression tri(C_(α)-C_(β) alkyl)silyl herein means a silyl group substituted with previously mentioned alkyl groups containing from α to β carbon atoms which may be identical with or different from one another, such as a trimethylsilyl group, a triethylsilyl group, a tri(n-propyl)silyl group, an ethyldimethylsilyl group, a n-propyldimethylsilyl group, a n-butyldimethylsilyl group, an i-butyldimethylsilyl group or a t-butyldimethylsilyl group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkylsulfonyloxy herein means an alkylsulfonyl-O— group in which the alkylsulfonyl means a previously mentioned alkylsulfonyl group containing from α to β carbon atoms, such as a methylsulfonyloxy group, an ethylsulfonyloxy group, a n-propylsulfonyloxy group or an i-propylsulfonyloxy group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) haloalkylsulfonyloxy herein means a haloalkylsulfonyl-O-group in which the haloalkylsulfonyl means a previously mentioned haloalkylsulfonyl group containing from α to β carbon atoms, such as a difluoromethylsulfonyloxy group, a trifluoromethylsulfonyloxy group, a chlorodifluoromethylsulfonyloxy group or a bromodifluoromethylsulfonyloxy group, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkoxy (C_(δ)-C_(ε)) alkyl herein means a previously mentioned alkyl group containing from δ to ε carbon atoms in which hydrogen atom(s) on carbon atom(s) are optionally substituted with previously mentioned alkoxy group(s) containing from α to β carbon atoms, and those within the designated carbon atom range are selected.

The expression C_(α)-C_(β) alkoxy(C_(δ)-C_(ε)) alkoxy herein means a previously mentioned alkoxy group containing from δ to ε carbon atoms in which hydrogen atom(s) on carbon atom(s) are optionally substituted with previously mentioned alkoxy group(s) containing from α to β carbon atoms, and those within the designated carbon atom range are selected.

The expression (C_(α)-C_(β)) alkenyl optionally substituted with a halogen atom or (C_(α)-C_(β)) alkenyl optionally substituted with R³¹ herein means a previously mentioned alkynyl group containing from α to β carbon atoms in which hydrogen atom(s) on carbon atom(s) are substituted with optional halogen atom(s) or R³¹, and those within the designated carbon atom range are selected. When there are two or more halogen atoms or the substituent R³¹'s on an (C_(α)-C_(β)) alkenyl group, the R³¹'s or the halogen atoms may be identical with or different from one another.

The expression benzyl having a benzene ring optionally substituted with e R²¹'s, benzyl having a benzene ring which may be substituted with f R²²'s or benzyl having a benzene ring which may be substituted with g R¹⁵'s herein means a previously mentioned benzyl group in which the hydrogen atoms on e, f or g carbon atom(s) in the benzene ring are optionally substituted with optional R²¹'s, R²²'s or R¹⁵'s. When there are two or more R²¹'s, R²²'s or R¹⁵'s in the benzene ring, they may be identical with or different from one another.

The expression phenyl optionally substituted with e R²¹'s, phenyl which may be substituted with f R²²'s or phenyl optionally substituted with k R⁸¹'s herein means a previously mentioned phenyl group in which the hydrogen atoms on e, f, or k carbon atoms in the benzene ring are optionally substituted with optional R²¹'s, R²²'s or R⁸¹'s. When there are two or more R²¹'s, R²²'s or R⁸¹'s in the benzene ring, they may be identical with or different from one another.

The expression 1-phenethyl having a benzene ring which may optionally be substituted with b R¹⁴'s herein means a 1-phenethyl group having a benzene ring in which the hydrogen atoms on b carbon atoms are optionally substituted with optional R¹⁴'s. When there are two or more R¹⁴'s in the benzene ring, they may be identical with or different from one another.

The expression 2-phenethyl having a benzene ring which may optionally be substituted with b R¹⁴'s herein means a 2-phenethyl group having a benzene ring in which the hydrogen atoms on b carbon atoms are optionally substituted with optional R¹⁴'s. When there are two or more R¹⁴'s in the benzene ring, they may be identical with or different from one another.

The expression (C_(α)-C_(β)) alkyl substituted with R¹⁷ herein means a previously mentioned alkyl group containing from α to β carbon atoms in which hydrogen atom(s) on carbon atom(s) are optionally substituted with R¹⁷, and those within the designated carbon atom range are selected. When there are two or more R¹⁷'s on an alkyl group on the (C_(α)-C_(β)) alkyl group, the R¹⁷'s may be identical with or different from one another.

As the scope of the substituent represented by R¹ in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R¹-I: C₁-C₆ alkyl.

R¹-II: C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, phenyl and phenyl substituted with a R¹¹'s [wherein R¹¹ is a halogen atom, C₁-C₆ alkyl or C₁-C₆ alkoxy, and when a is an integer of at least two, each R¹¹ may be identical with or different from one another, R¹² is C₁-C₆ alkyl, R¹⁷ is —C(O)OR¹² or phenyl, and a is an integer of from 1 to 5].

R¹-III: C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, D5, phenyl and phenyl substituted with a R¹¹'s [wherein R¹¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy or nitro, and when a is an integer of at least two, each R¹¹ may be identical with or different from one another, and when there are two neighboring R¹¹'s, the two neighboring R¹¹'s may form —CH═CHCH═CH— to form a 6-membered ring together with the carbon atoms attached to the two R¹¹'s, R^(z) is a halogen atom or C₁-C₆ alkyl, R¹² is C₁-C₆ alkyl, R¹⁷ is —C(O)O R¹² or phenyl, a is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

R¹-IV: C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)O R¹², D2, D4, D5, D7, D21, D22, D23, phenyl and phenyl substituted with a R¹¹'s [wherein R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀haloalkyl, C₁-C₁₀ haloalkoxy, nitro or phenyl, R¹² is a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, and when there are two neighboring R¹¹'s, the two neighboring R¹¹'s may form, together with the carbon atoms attached to the two R¹¹'s, —CH═CHCH═CH— to form a 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R¹² is a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, R¹⁷ is −0(O)OR¹² or phenyl, Z is a halogen atom or C₁-C₆ alkyl, Ry is C₁-C₆ alkyl or phenyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, when s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, a is an integer of from 1 to 5, m is an integer of from 1 to 5, s2 is an integer of from 0 to 3, and s3 is an integer of from 0 to 2].

As the scope of the substituent represented by R² in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R²-I: a hydrogen atom, C₁-C₆ alkyl, phenyl and phenyl optionally substituted with e R²¹'s [wherein R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₁-C₆ haloalkyl or phenyl, and when e is an integer of at least 2, each R²¹ may be identical with or different from one another, and e is an integer of from 1 to 5].

R²-II: a hydrogen atom, C₁-C₆ alkyl, D2, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl and phenyl optionally substituted with e R²¹'s [wherein R²¹ is a halogen atom, C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₁-C₆ haloalkyl, nitro, cyano or phenyl, when e is an integer of at least 2, each R²¹ may be identical with or different from one another, and when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, Z is a halogen atom or C₁-C₆ alkyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy or phenyl, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, e is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

R²-III: a hydrogen atom, C₁-C₆ alkyl, D2, D7, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl and phenyl optionally substituted with e R²¹'s [wherein R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, nitro, cyano, phenoxy, phenyl or phenyl which may be substituted with f R²²'s, and when f is an integer of at least 2, each R²² may be identical with or different from one another, and when e is an integer of at least 2, each R²¹ may be identical with or different from one another, and when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R²² is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, Z is a halogen atom or C₁-C₆ alkyl, and when f is an integer of at least 2, each R²² may be identical with or different from one another, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s2 is an integer of at least 2, each R_(z) may be identical with or different from one another, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, e is an integer of from 1 to 5, f is an integer of from 1 to 5, m is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

R²-IV: a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D2, D7, benzyl, benzyl having a benzene ring optionally substituted with e R²¹'s, phenyl and phenyl optionally substituted with e R²¹'s [wherein R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₃₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, nitro, cyano, phenoxy, phenyl or phenyl which may be substituted with f R²²'s, and when f is an integer of at least 2, each R²² may be identical with or different from one another, and when e is an integer of at least 2, each R²¹ may be identical with or different from one another, and when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R²² is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, Z is a halogen atom or C₁-C₆ alkyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, e is an integer of from 1 to 5, f is an integer of from 1 to 5, e is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

As the scope of the substituent represented by R³ in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R³-I: a hydrogen atom.

R³-II: a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹² and —C(O)N(R¹²)R¹³ [wherein each of R¹² and R¹³ is independently a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl], —Si(R³²)(R³³)R³⁴ [wherein each of R³², R³³ and R³⁴ is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl].

R³-III: a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹² and —C(O)N(R¹²)R¹³ [wherein each of R¹² and R¹³ is independently a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl], —Si(R³²)(R³³)R³⁴ [wherein each of R³², R³³ and R³⁴ is independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl], benzyl or benzyl having a benzene ring which may be substituted with g R¹⁵'s [wherein R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, and when g is an integer of at least 2, each R¹⁵ may be identical with or different from one another, and g is an integer of from 1 to 5].

As the scope of the substituent represented by R⁴ in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R⁴-I: C₁-C₄ alkyl.

As the scope of the substituent represented by R⁵ in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R⁵-I: C₁-C₄ alkyl_(o)

As the scope of the substituent represented by R⁴ and R⁵ in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R⁴+R⁵: —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂CH₂—, which forms a 3-membered, 4-membered, 5-membered or 6-membered ring together with the carbon atoms attached to R⁴ and R⁵.

As the scope of the substituent represented by R⁸ in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

R⁸-I: F1, phenyl, 1-naphthyl or 2-naphthyl.

R⁸-II: D2, F1, phenyl and phenyl optionally substituted with k R⁸¹'s [wherein R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, phenyl or phenoxy, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy or phenyl, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, k is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

R⁸-III: D2, F1, phenyl and phenyl optionally substituted with k R⁸¹'s [wherein R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl or phenoxy, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom or C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, k is an integer of from 1 to 5, m is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

R⁸-IV: D2, D7, D23, F1, F2, phenyl and phenyl optionally substituted with k R⁸¹s [wherein R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl or phenoxy, and when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and when there are two neighboring R⁸¹'s, the two neighboring R⁸¹'s may form —OCH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹'s, a 5-membered or 6-membered ring which may have one or more hydrogen atoms on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with m R¹⁶'s, and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, and when s2 is an integer of at least 2, each R^(z) may be identical with or different from one another, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, k is an integer of from 1 to 5, m is an integer of from 1 to 5, and s2 is an integer of from 0 to 3].

As the scope of the substituent represented by X in the compounds which fall within the present invention, the following sets may, for example, be mentioned.

X-1: a single bond.

X-2: —CH₂—.

The sets indicating the scope of each substituent in the compounds which fall within the present invention may be combined arbitrarily to indicate the scope of the compounds of the present invention. The scope of R¹, R², R³, R⁸ or X may be combined, for example, as shown in Table 1. The combinations shown in Table 1 merely exemplify the present invention, and the present invention is by no means restricted thereto.

TABLE 1 R¹ R² R³ R⁸ X R¹-I R²-I R³-I R⁸-I X-1 R¹-I R²-I R³-I R⁸-II X-1 R¹-I R²-I R³-I R⁸-III X-1 R¹-I R²-I R³-I R⁸-IV X-1 R¹-I R²-I R³-II R⁸-I X-1 R¹-I R²-I R³-II R⁸-II X-1 R¹-I R²-I R³-II R⁸-III X-1 R¹-I R²-I R³-II R⁸-IV X-1 R¹-I R²-I R³-III R⁸-I X-1 R¹-I R²-I R³-III R⁸-II X-1 R¹-I R²-I R³-III R⁸-III X-1 R¹-I R²-I R³-III R⁸-IV X-1 R¹-I R²-II R³-I R⁸-I X-1 R¹-I R²-II R³-I R⁸-II X-1 R¹-I R²-II R³-I R⁸-III X-1 R¹-I R²-II R³-I R⁸-IV X-1 R¹-I R²-II R³-II R⁸-I X-1 R¹-I R²-II R³-II R⁸-II X-1 R¹-I R²-II R³-II R⁸-III X-1 R¹-I R²-II R³-II R⁸-IV X-1 R¹-I R²-II R³-III R⁸-I X-1 R¹-I R²-II R³-III R⁸-II X-1 R¹-I R²-II R³-III R⁸-III X-1 R¹-I R²-II R³-III R⁸-IV X-1 R¹-I R²-III R³-I R⁸-I X-1 R¹-I R²-III R³-I R⁸-II X-1 R¹-I R²-III R³-I R⁸-III X-1 R¹-I R²-III R³-I R⁸-IV X-1 R¹-I R²-III R³-II R⁸-I X-1 R¹-I R²-III R³-II R⁸-II X-1 R¹-I R²-III R³-II R⁸-III X-1 R¹-I R²-III R³-II R⁸-IV X-1 R¹-I R²-III R³-III R⁸-I X-1 R¹-I R²-III R³-III R⁸-II X-1 R¹-I R²-III R³-III R⁸-III X-1 R¹-I R²-III R³-III R⁸-IV X-1 R¹-I R²-IV R³-I R⁸-I X-1 R¹-I R²-IV R³-I R⁸-II X-1 R¹-I R²-IV R³-I R⁸-III X-1 R¹-I R²-IV R³-I R⁸-IV X-1 R¹-I R²-IV R³-II R⁸-I X-1 R¹-I R²-IV R³-II R⁸-II X-1 R¹-I R²-IV R³-II R⁸-III X-1 R¹-I R²-IV R³-II R⁸-IV X-1 R¹-I R²-IV R³-III R⁸-I X-1 R¹-I R²-IV R³-III R⁸-II X-1 R¹-I R²-IV R³-III R⁸-III X-1 R¹-I R²-IV R³-III R⁸-IV X-1 R¹-II R²-I R³-I R⁸-I X-1 R¹-II R²-I R³-I R⁸-II X-1 R¹-II R²-I R³-I R⁸-III X-1 R¹-II R²-I R³-I R⁸-IV X-1 R¹-II R²-I R³-II R⁸-I X-1 R¹-II R²-I R³-II R⁸-II X-1 R¹-II R²-I R³-II R⁸-III X-1 R¹-II R²-I R³-II R⁸-IV X-1 R¹-II R²-I R³-III R⁸-I X-1 R¹-II R²-I R³-III R⁸-II X-1 R¹-II R²-I R³-III R⁸-III X-1 R¹-II R²-I R³-III R⁸-IV X-1 R¹-II R²-II R³-I R⁸-I X-1 R¹-II R²-II R³-I R⁸-II X-1 R¹-II R²-II R³-I R⁸-III X-1 R¹-II R²-II R³-I R⁸-IV X-1 R¹-II R²-II R³-II R⁸-I X-1 R¹-II R²-II R³-II R⁸-II X-1 R¹-II R²-II R³-II R⁸-III X-1 R¹-II R²-II R³-II R⁸-IV X-1 R¹-II R²-II R³-III R⁸-I X-1 R¹-II R²-II R³-III R⁸-II X-1 R¹-II R²-II R³-III R⁸-III X-1 R¹-II R²-II R³-III R⁸-IV X-1 R¹-II R²-III R³-I R⁸-I X-1 R¹-II R²-III R³-I R⁸-II X-1 R¹-II R²-III R³-I R⁸-III X-1 R¹-II R²-III R³-I R⁸-IV X-1 R¹-II R²-III R³-II R⁸-I X-1 R¹-II R²-III R³-II R⁸-II X-1 R¹-II R²-III R³-II R⁸-III X-1 R¹-II R²-III R³-II R⁸-IV X-1 R¹-II R²-III R³-III R⁸-I X-1 R¹-II R²-III R³-III R⁸-II X-1 R¹-II R²-III R³-III R⁸-III X-1 R¹-II R²-III R³-III R⁸-IV X-1 R¹-II R²-IV R³-I R⁸-I X-1 R¹-II R²-IV R³-I R⁸-II X-1 R¹-II R²-IV R³-I R⁸-III X-1 R¹-II R²-IV R³-I R⁸-IV X-1 R¹-II R²-IV R³-II R⁸-I X-1 R¹-II R²-IV R³-II R⁸-II X-1 R¹-II R²-IV R³-II R⁸-III X-1 R¹-II R²-IV R³-II R⁸-IV X-1 R¹-II R²-IV R³-III R⁸-I X-1 R¹-II R²-IV R³-III R⁸-II X-1 R¹-II R²-IV R³-III R⁸-III X-1 R¹-II R²-IV R³-III R⁸-IV X-1 R¹-III R²-I R³-I R⁸-I X-1 R¹-III R²-I R³-I R⁸-II X-1 R¹-III R²-I R³-I R⁸-III X-1 R¹-III R²-I R³-I R⁸-IV X-1 R¹-III R²-I R³-II R⁸-I X-1 R¹-III R²-I R³-II R⁸-II X-1 R¹-III R²-I R³-II R⁸-III X-1 R¹-III R²-I R³-II R⁸-IV X-1 R¹-III R²-I R³-III R⁸-I X-1 R¹-III R²-I R³-III R⁸-II X-1 R¹-III R²-I R³-III R⁸-III X-1 R¹-III R²-I R³-III R⁸-IV X-1 R¹-III R²-II R³-I R⁸-I X-1 R¹-III R²-II R³-I R⁸-II X-1 R¹-III R²-II R³-I R⁸-III X-1 R¹-III R²-II R³-I R⁸-IV X-1 R¹-III R²-II R³-II R⁸-I X-1 R¹-III R²-II R³-II R⁸-II X-1 R¹-III R²-II R³-II R⁸-III X-1 R¹-III R²-II R³-II R⁸-IV X-1 R¹-III R²-II R³-III R⁸-I X-1 R¹-III R²-II R³-III R⁸-II X-1 R¹-III R²-II R³-III R⁸-III X-1 R¹-III R²-II R³-III R⁸-IV X-1 R¹-III R²-III R³-I R⁸-I X-1 R¹-III R²-III R³-I R⁸-II X-1 R¹-III R²-III R³-I R⁸-III X-1 R¹-III R²-III R³-I R⁸-IV X-1 R¹-III R²-III R³-II R⁸-I X-1 R¹-III R²-III R³-II R⁸-II X-1 R¹-III R²-III R³-II R⁸-III X-1 R¹-III R²-III ³-II R⁸-IV X-1 R¹-III R²-III R³-III R⁸-I X-1 R¹-III R²-III R³-III R⁸-II X-1 R¹-III R²-III R³-III R⁸-III X-1 R¹-III R²-III R³-III R⁸-IV X-1 R¹-III R²-IV R³-I R⁸-I X-1 R¹-III R²-IV R³-I R⁸-II X-1 R¹-III R²-IV R³-I R⁸-III X-1 R¹-III R²-IV R³-I R⁸-IV X-1 R¹-III R²-IV R³-II R⁸-I X-1 R¹-III R²-IV R³-II R⁸-II X-1 R¹-III R²-IV R³-II R⁸-III X-1 R¹-III R²-IV R³-II R⁸-IV X-1 R¹-III R²-IV R³-III R⁸-I X-1 R¹-III R²-IV R³-III R⁸-II X-1 R¹-III R²-IV R³-III R⁸-III X-1 R¹-III R²-IV R³-III R⁸-IV X-1 R¹-IV R²-I R³-I R⁸-I X-1 R¹-IV R²-I R³-I R⁸-II X-1 R¹-IV R²-I R³-I R⁸-III X-1 R¹-IV R²-I R³-I R⁸-IV X-1 R¹-IV R²-I R³-II R⁸-I X-1 R¹-IV R²-I R³-II R⁸-II X-1 R¹-IV R²-I R³-II R⁸-III X-1 R¹-IV R²-I R³-II R⁸-IV X-1 R¹-IV R²-I R³-III R⁸-I X-1 R¹-IV R²-I R³-III R⁸-II X-1 R¹-IV R²-I R³-III R⁸-III X-1 R¹-IV R²-I R³-III R⁸-IV X-1 R¹-IV R²-II R³-I R⁸-I X-1 R¹-IV R²-II R³-I R⁸-II X-1 R¹-IV R²-II R³-I R⁸-III X-1 R¹-IV R²-II R³-I R⁸-IV X-1 R¹-IV R²-II R³-II R⁸-I X-1 R¹-IV R²-II R³-II R⁸-II X-1 R¹-IV R²-II R³-II R⁸-III X-1 R¹-IV R²-II R³-II R⁸-IV X-1 R¹-IV R²-II R³-III R⁸-I X-1 R¹-IV R²-II R³-III R⁸-II X-1 R¹-IV R²-II R³-III R⁸-III X-1 R¹-IV R²-II R³-III R⁸-IV X-1 R¹-IV R²-III R³-I R⁸-I X-1 R¹-IV R²-III R³-I R⁸-II X-1 R¹-IV R²-III R³-I R⁸-III X-1 R¹-IV R²-III R³-I R⁸-IV X-1 R¹-IV R²-III R³-II R⁸-I X-1 R¹-IV R²-III R³-II R⁸-II X-1 R¹-IV R²-III R³-II R⁸-III X-1 R¹-IV R²-III R³-II R⁸-IV X-1 R¹-IV R²-III R³-III R⁸-I X-1 R¹-IV R²-III R³-III R⁸-II X-1 R¹-IV R²-III R³-III R⁸-III X-1 R¹-IV R²-III R³-III R⁸-IV X-1 R¹-IV R²-IV R³-I R⁸-I X-1 R¹-IV R²-IV R³-I R⁸-II X-1 R¹-IV R²-IV R³-I R⁸-III X-1 R¹-IV R²-IV R³-I R⁸-IV X-1 R¹-IV R²-IV R³-II R⁸-I X-1 R¹-IV R²-IV R³-II R⁸-II X-1 R¹-IV R²-IV R³-II R⁸-III X-1 R¹-IV R²-IV R³-II R⁸-IV X-1 R¹-IV R²-IV R³-III R⁸-I X-1 R¹-IV R²-IV R³-III R⁸-II X-1 R¹-IV R²-IV R³-III R⁸-III X-1 R¹-IV R²-IV R³-III R⁸-IV X-1 R¹-I R²-I R³-I R⁸-I X-2 R¹-I R²-I R³-I R⁸-II X-2 R¹-I R²-I R³-I R⁸-III X-2 R¹-I R²-I R³-I R⁸-IV X-2 R¹-I R²-I R³-II R⁸-I X-2 R¹-I R²-I R³-II R⁸-II X-2 R¹-I R²-I R³-II R⁸-III X-2 R¹-I R²-I R³-II R⁸-IV X-2 R¹-I R²-I R³-III R⁸-I X-2 R¹-I R²-I R³-III R⁸-II X-2 R¹-I R²-I R³-III R⁸-III X-2 R¹-I R²-I R³-III R⁸-IV X-2 R¹-I R²-II R³-I R⁸-I X-2 R¹-I R²-II R³-I R⁸-II X-2 R¹-I R²-II R³-I R⁸-III X-2 R¹-I R²-II R³-I R⁸-IV X-2 R¹-I R²-II R³-II R⁸-I X-2 R¹-I R²-II R³-II R⁸-II X-2 R¹-I R²-II R³-II R⁸-III X-2 R¹-I R²-II R³-II R⁸-IV X-2 R¹-I R²-II R³-III R⁸-I X-2 R¹-I R²-II R³-III R⁸-II X-2 R¹-I R²-II R³-III R⁸-III X-2 R¹-I R²-II R³-III R⁸-IV X-2 R¹-I R²-III R³-I R⁸-I X-2 R¹-I R²-III R³-I R⁸-II X-2 R¹-I R²-III R³-I R⁸-III X-2 R¹-I R²-III R³-I R⁸-IV X-2 R¹-I R²-III R³-II R⁸-I X-2 R¹-I R²-III R³-II R⁸-II X-2 R¹-I R²-III R³-II R⁸-III X-2 R¹-I R²-III R³-II R⁸-IV X-2 R¹-I R²-III R³-III R⁸-I X-2 R¹-I R²-III R³-III R⁸-II X-2 R¹-I R²-III R³-III R⁸-III X-2 R¹-I R²-III R³-III R⁸-IV X-2 R¹-I R²-IV R³-I R⁸-I X-2 R¹-I R²-IV R³-I R⁸-II X-2 R¹-I R²-IV R³-I R⁸-III X-2 R¹-I R²-IV R³-I R⁸-IV X-2 R¹-I R²-IV R³-II R⁸-I X-2 R¹-I R²-IV R³-II R⁸-II X-2 R¹-I R²-IV R³-II R⁸-III X-2 R¹-I R²-IV R³-II R⁸-IV X-2 R¹-I R²-IV R³-III R⁸-I X-2 R¹-I R²-IV R³-III R⁸-II X-2 R¹-I R²-IV R³-III R⁸-III X-2 R¹-I R²-IV R³-III R⁸-IV X-2 R¹-II R²-I R³-I R⁸-I X-2 R¹-II R²-I R³-I R⁸-II X-2 R¹-II R²-I R³-I R⁸-III X-2 R¹-II R²-I R³-I R⁸-IV X-2 R¹-II R²-I R³-II R⁸-I X-2 R¹-II R²-I R³-II R⁸-II X-2 R¹-II R²-I R³-II R⁸-III X-2 R¹-II R²-I R³-II R⁸-IV X-2 R¹-II R²-I R³-III R⁸-I X-2 R¹-II R²-I R³-III R⁸-II X-2 R¹-II R²-I R³-III R⁸-III X-2 R¹-II R²-I R³-III R⁸-IV X-2 R¹-II R²-II R³-I R⁸-I X-2 R¹-II R²-II R³-I R⁸-II X-2 R¹-II R²-II R³-I R⁸-III X-2 R¹-II R²-II R³-I R⁸-IV X-2 R¹-II R²-II R³-II R⁸-I X-2 R¹-II R²-II R³-II R⁸-II X-2 R¹-II R²-II R³-II R⁸-III X-2 R¹-II R²-II R³-II R⁸-IV X-2 R¹-II R²-II R³-III R⁸-I X-2 R¹-II R²-II R³-III R⁸-II X-2 R¹-II R²-II R³-III R⁸-III X-2 R¹-II R²-II R³-III R⁸-IV X-2 R¹-II R²-III R³-I R⁸-I X-2 R¹-II R²-III R³-I R⁸-II X-2 R¹-II R²-III R³-I R⁸-III X-2 R¹-II R²-III R³-I R⁸-IV X-2 R¹-II R²-III R³-II R⁸-I X-2 R¹-II R²-III R³-II R⁸-II X-2 R¹-II R²-III R³-II R⁸-III X-2 R¹-II R²-III R³-II R⁸-IV X-2 R¹-II R²-III R³-III R⁸-I X-2 R¹-II R²-III R³-III R⁸-II X-2 R¹-II R²-III R³-III R⁸-III X-2 R¹-II R²-III R³-III R⁸-IV X-2 R¹-II R²-IV R³-I R⁸-I X-2 R¹-II R²-IV R³-I R⁸-II X-2 R¹-II R²-IV R³-I R⁸-III X-2 R¹-II R²-IV R³-I R⁸-IV X-2 R¹-II R²-IV R³-II R⁸-I X-2 R¹-II R²-IV R³-II R⁸-II X-2 R¹-II R²-IV R³-II R⁸-III X-2 R¹-II R²-IV R³-II R⁸-IV X-2 R¹-II R²-IV R³-III R⁸-I X-2 R¹-II R²-IV R³-III R⁸-II X-2 R¹-II R²-IV R³-III R⁸-III X-2 R¹-II R²-IV R³-III R⁸-IV X-2 R¹-III R²-I R³-I R⁸-I X-2 R¹-III R²-I R³-I R⁸-II X-2 R¹-III R²-I R³-I R⁸-III X-2 R¹-III R²-I R³-I R⁸-IV X-2 R¹-III R²-I R³-II R⁸-I X-2 R¹-III R²-I R³-II R⁸-II X-2 R¹-III R²-I R³-II R⁸-III X-2 R¹-III R²-I R³-II R⁸-IV X-2 R¹-III R²-I R³-III R⁸-I X-2 R¹-III R²-I R³-III R⁸-II X-2 R¹-III R²-I R³-III R⁸-III X-2 R¹-III R²-I R³-III R⁸-IV X-2 R¹-III R²-II R³-I R⁸-I X-2 R¹-III R²-II R³-I R⁸-II X-2 R¹-III R²-II R³-I R⁸-III X-2 R¹-III R²-II R³-I R⁸-IV X-2 R¹-III R²-II R³-II R⁸-I X-2 R¹-III R²-II R³-II R⁸-II X-2 R¹-III R²-II R³-II R⁸-III X-2 R¹-III R²-II R³-II R⁸-IV X-2 R¹-III R²-II R³-III R⁸-I X-2 R¹-III R²-II R³-III R⁸-II X-2 R¹-III R²-II R³-III R⁸-III X-2 R¹-III R²-II R³-III R⁸-IV X-2 R¹-III R²-III R³-I R⁸-I X-2 R¹-III R²-III R³-I R⁸-II X-2 R¹-III R²-III R³-I R⁸-III X-2 R¹-III R²-III R³-I R⁸-IV X-2 R¹-III R²-III R³-II R⁸-I X-2 R¹-III R²-III R³-II R⁸-II X-2 R¹-III R²-III R³-II R⁸-III X-2 R¹-III R²-III R³-II R⁸-IV X-2 R¹-III R²-III R³-III R⁸-I X-2 R¹-III R²-III R³-III R⁸-II X-2 R¹-III R²-III R³-III R⁸-III X-2 R¹-III R²-III R³-III R⁸-IV X-2 R¹-III R²-IV R³-I R⁸-I X-2 R¹-III R²-IV R³-I R⁸-II X-2 R¹-III R²-IV R³-I R⁸-III X-2 R¹-III R²-IV R³-I R⁸-IV X-2 R¹-III R²-IV R³-II R⁸-I X-2 R¹-III R²-IV R³-II R⁸-II X-2 R¹-III R²-IV R³-II R⁸-III X-2 R¹-III R²-IV R³-II R⁸-IV X-2 R¹-III R²-IV R³-III R⁸-I X-2 R¹-III R²-IV R³-III R⁸-II X-2 R¹-III R²-IV R³-III R⁸-III X-2 R¹-III R²-IV R³-III R⁸-IV X-2 R¹-IV R²-I R³-I R⁸-I X-2 R¹-IV R²-I R³-I R⁸-II X-2 R¹-IV R²-I R³-I R⁸-III X-2 R¹-IV R²-I R³-I R⁸-IV X-2 R¹-IV R²-I R³-II R⁸-I X-2 R¹-IV R²-I R³-II R⁸-II X-2 R¹-IV R²-I R³-II R⁸-III X-2 R¹-IV R²-I R³-II R⁸-IV X-2 R¹-IV R²-I R³-III R⁸-I X-2 R¹-IV R²-I R³-III R⁸-II X-2 R¹-IV R²-I R³-III R⁸-III X-2 R¹-IV R²-I R³-III R⁸-IV X-2 R¹-IV R²-II R³-I R⁸-I X-2 R¹-IV R²-II R³-I R⁸-II X-2 R¹-IV R²-II R³-I R⁸-III X-2 R¹-IV R²-II R³-I R⁸-IV X-2 R¹-IV R²-II R³-II R⁸-I X-2 R¹-IV R²-II R³-II R⁸-II X-2 R¹-IV R²-II R³-II R⁸-III X-2 R¹-IV R²-II R³-II R⁸-IV X-2 R¹-IV R²-II R³-III R⁸-I X-2 R¹-IV R²-II R³-III R⁸-II X-2 R¹-IV R²-II R³-III R⁸-III X-2 R¹-IV R²-II R³-III R⁸-IV X-2 R¹-IV R²-III R³-I R⁸-I X-2 R¹-IV R²-III R³-I R⁸-II X-2 R¹-IV R²-III R³-I R⁸-III X-2 R¹-IV R²-III R³-I R⁸-IV X-2 R¹-IV R²-III R³-II R⁸-I X-2 R¹-IV R²-III R³-II R⁸-II X-2 R¹-IV R²-III R³-II R⁸-III X-2 R¹-IV R²-III R³-II R⁸-IV X-2 R¹-IV R²-III R³-III R⁸-I X-2 R¹-IV R²-III R³-III R⁸-II X-2 R¹-IV R²-III R³-III R⁸-III X-2 R¹-IV R²-III R³-III R⁸-IV X-2 R¹-IV R²-IV R³-I R⁸-I X-2 R¹-IV R²-IV R³-I R⁸-II X-2 R¹-IV R²-IV R³-I R⁸-III X-2 R¹-IV R²-IV R³-I R⁸-IV X-2 R¹-IV R²-IV R³-II R⁸-I X-2 R¹-IV R²-IV R³-II R⁸-II X-2 R¹-IV R²-IV R³-II R⁸-III X-2 R¹-IV R²-IV R³-II R⁸-IV X-2 R¹-IV R²-IV R³-III R⁸-I X-2 R¹-IV R²-IV R³-III R⁸-II X-2 R¹-IV R²-IV R³-III R⁸-III X-2 R¹-IV R²-IV R³-III R⁸-IV X-2

The compounds of the present invention can be produced, for example, by the following processes.

A compound represented by the formula (11) [wherein R¹, R², R⁴, R⁵, R⁸ and X are the same as defined above] and a compound represented by the formula (12)[wherein R³ is the same as defined above, and J¹ is a chlorine atom, a bromine atom, an iodine atom, a halosulfonyloxy group (such as a fluorosulfonyloxy group), a C₁-C₄ haloalkylsulfonyloxy group (such as a trifluoromethanesulfonyloxy group) or an arylsulfonyloxy group (such as a benzenesulfonyloxy group)] may be reacted, if necessary in the presence of a base, if necessary by using a solvent inert to the reaction, to obtain a compound of the present invention represented by the formula (1) [wherein R¹, R², R³, R⁴, R⁵, R⁸ and X are the same as defined above].

Regarding the amounts of the reactants, from 1 to 50 equivalents of the compound represented by the formula (12) may be used per 1 equivalent of the compound represented by the formula (11).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide such as dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

As the base, if used, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal hydroxide such as hydroxide or potassium hydroxide, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, an alkali metal amide such as lithium diidopropylamide, lithium diisopropylamide, lithium hexamethyldisilazane or sodium amide, an organic metal compound such as t-butyllithium, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, an organic base such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine or imidazole, 1,8-diazabicyclo[5,4,0]-7-undecene or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (11).

The reaction temperature may be set arbitrarily within the range of from −60° C. to the refluxing temperature of the reaction mixture, and the reaction time may be set arbitrarily within the range of from 5 minutes to 100 hours, though it depends on the concentrations of the reactants and the reaction temperature.

In general, the reaction is preferably carried out by using from 1 to 10 equivalents of a compound represented by the formula (12) per 1 equivalent of a compound represented by the formula (11) in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, chloroform, methylene chloride or toluene, if necessary by using from 1 to 3 equivalents of a base such as sodium hydride, potassium t-butoxide, potassium hydroxide, potassium carbonate, triethylamine or pyridine per 1 equivalent of the compound represented by the formula (11) at 0˜100° C. for 10 minutes to 24 hours.

A compound represented by the formula (13) [wherein R⁴, R⁵, R⁸ and X are the same as defined above] and a compound represented by the formula (14) [wherein R¹ and R² are the same as defined above, and J² is an alkyl group such as a methyl group or an ethyl group] are reacted, if necessary in the presence of an acid, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as WO 2005/061462 to obtain a compound of the present invention represented by the formula (1) [wherein R¹, R², R⁴, R⁵, R⁸ and X are the same as defined above].

Regarding the amounts of the reactants, from 1 to 50 equivalents of the compound represented by the formula (13) may be used per 1 equivalent of the compound represented by the formula (14).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide such as dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

As an acid, if used, a mineral acid such as hydrochloric acid or sulfuric acid, a carboxylic acid such as formic acid, acetic acid, trifluoroacetic acid, mandelic acid or tartaric acid, a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid, benzensulfonic acid, trifluoromethanesulfonic acid or camphor sulfonic acid, phosphorus oxychloride, Amberlite IR-120 (type H) or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (14).

The reaction temperature may be set arbitrarily within the range of from −60° C. to the refluxing temperature of the reaction mixture, and the reaction time may be set arbitrarily within the range of from 5 minutes to 100 hours, though it depends on the concentrations of the reactants and the reaction temperature.

In general, the reaction is preferably carried out by using from 1 to 10 equivalents of a compound represented by the formula (13) per 1 equivalent of a compound represented by the formula (14) in a solvent such as ethanol, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, chloroform or methylene chloride, if necessary by using from 1 to 3 equivalents of an acid such as acetic acid, p-toluenesulfonic acid or hydrochloric acid at 0-100° C. for 10 minutes to 24 hours.

Some of the keto esters represented by the formula (15) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized from known compounds by known methods disclosed in the literature such as JP-A-2002-020366, J. Med. Chem., 2005, vol. 48, pages 3400.

A compound represented by the formula (15) obtainable by Process A and a compound represented by the formula (17) [wherein R¹, R⁴, R⁵, R⁸, R¹² and X are the same as defined above] are reacted, if necessary in the presence of a base, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as WO2007/142308 to obtain a compound of the present invention represented by the formula (16) [wherein R¹¹, R⁴, R⁵, R⁸, R¹² and X are the same as defined above].

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide suchas dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

As the base, if used, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal hydroxide such as hydroxide or potassium hydroxide, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, an alkali metal amide such as lithium diidopropylamide, lithium diidopropylamide, lithium hexamethyldisilazane or sodium amide, an organic metal compound such as t-butyllithium, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, an organic base such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine or imidazole, 1,8-diazabicyclo[5,4,0]-7-undecene or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (15) or (17).

The reaction temperature may be set arbitrarily within the range of from −60° C. to the refluxing temperature of the reaction mixture, and the reaction time may be set arbitrarily within the range of from 5 minutes to 100 hours, though it depends on the concentrations of the reactants and the reaction temperature.

In general, the reaction is preferably carried out by using 1 equivalent of a compound represented by the formula (15) or (17) in a solvent such as ethanol, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, chloroform or methylene chloride, if necessary by using from 1 to 3 equivalents of a base such as sodium hydride, potassium t-butoxide, potassium hydroxide, potassium carbonate, triethylamine or pyridine per 1 equivalent of the compound represented by the formula (15) or (17) at 0-100° C. for 10 minutes to 24 hours.

A compound represented by the formula (41) [wherein R¹, R³, R⁴, R⁵, R⁸ and X are the same as defined above, and J³ is a chlorine atom, a bromine atom, an iodine atom or the like] and a compound represented by the formula (42) [wherein R² is the same as defined above, and J⁴ is dihydroxyborane or the like] are reacted, if necessary in the presence of a metal catalyst, if necessary in the presence of a base, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as WO 2010/0794432 to obtain a compound of the present invention represented by the formula (1) [wherein R¹, R², R³, R⁴, R⁵, R⁸ and X are the same as defined above].

Regarding the amounts of the reactants, from 1 to 50 equivalents of the compound represented by the formula (42) may be used per 1 equivalent of the compound represented by the formula (41).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide suchas dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

As the base, if used, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal hydroxide such as hydroxide or potassium hydroxide, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, an alkali metal amide such as lithium diidopropylamide, lithium diidopropylamide, lithium hexamethyldisilazane or sodium amide, an organic metal compound such as t-butyllithium, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, an organic base such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine or imidazole, 1,8-diazabicyclo[5,4,0]-7-undecene or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (41) or (42).

As the metal catalyst, if use, a palladium hydroxide catalyst such as Pd(OH)₂, a palladium oxide catalyst such as PdO, a palladium halide catalyst such as PdBr₂, PdCl₂ or PdI₂, a palladium acetate catalyst suchas palladium acetate (Pd(OAc)₂) or palladium trifluoroacetate (Pd(OCOCF₃)₂), a palladium metal complex catalyst having a ligand such as Pd(RNC)₂Cl₂, Pd(acac)₂, diacetate bis(triphenylphosphine)palladium [Pd(OAc)₂ (PPh₃)₂], Pd(PPh₃, Pd₂ (dba)₃, Pd(NH₃)₂, Pd(CH₃CN)₂Cl₂, dichlorobis (benzonitrile)palladium [Pd(PhCN)₂Cl₂], Pd(dppe)Cl₂, Pd(dppf)Cl₂, Pd[PCy₃]₂Cl₂, Pd(PPh₃)₂Cl₂, Pd[P(o-tolyl)₃]₂Cl₂, Pd(cod)₂Cl₂, Pd(PPh₃)(CH₃CN)₂Cl₂, Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) or the like may, for example, be mentioned.

Such a metal catalyst may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (41) or (42).

A compound represented by the formula (43) [wherein R¹, R³, R⁴, R⁵, R⁸ and X are the same as defined above] and a compound represented by the formula (44) [wherein R² is the same as defined above, and J⁵ is a chlorine atom, a bromine atom, an iodine atom or the like] are reacted, if necessary in the presence of a base, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as Bioorganic & Medicinal Chemistry, 2006, vol. 14, p. 5061 to obtain a compound of the present invention represented by the formula (1) [wherein R¹, R², R³, R⁴, R⁵, R⁸ and X are the same as defined above].

Regarding the amounts of the reactants, from 1 to 50 equivalents of the compound represented by the formula (44) may be used per 1 equivalent of the compound represented by the formula (43).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide such as dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

As the base, if used, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal hydroxide such as hydroxide, potassium hydroxide or calcium hydroxide, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, an alkali metal amide such as lithium diidopropylamide, lithium diisopropylamide, lithium hexamethyldisilazane or sodium amide, an organic metal compound such as t-butyllithium, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, an organic base such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine or imidazole, 1,8-diazabicyclo[5,4,0]-7-undecene or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (43) or (44).

A compound represented by the formula (45) [wherein R¹, R³, R⁴, R⁶, R⁸ and X are the same as defined above] is reacted, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as Bioorganic & Medicinal Chemistry, 2006, vol. 14, p. 5061 to obtain a compound of the present invention represented by the formula (1) [wherein R¹, R³, R⁴, R⁶, R⁸ and X are the same as defined above, and J⁶ is a chlorine atom, a bromine atom, an iodine atom or the like].

As the halogenation reagent, N-bromosuccinimide, N-chlorosuccinimide, chlorine, bromine, potassium iodide, sodium iodide or the like may be used.

Regarding the amounts of the reactants, from 1 to 50 equivalents of a halogenations reagent may be used per 1 equivalent of a compound represented by the formula (45).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide suchas dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions.

The reaction temperature may be set arbitrarily within the range of from −60° C. to the refluxing temperature of the reaction mixture, and the reaction time may be set arbitrarily within the range of from 5 minutes to 100 hours, though it depends on the concentrations of the reactants and the reaction temperature.

A compound represented by the formula (46) [wherein R¹, R³, R⁴, R⁵, R⁸, R¹² and X are the same as defined above] and a compound represented by the formula (47) are reacted, if necessary in the presence of a base, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as European Journal of Organic Chemistry, 2003, vol. 7, p. 1209 and Organic Letters, 2008, vol. 10, p. 1695 to obtain a compound of the present invention represented by the formula (48) [wherein R¹, R³, R⁴, R⁵, R⁸, R¹², R¹³ and X are the same as defined above].

Regarding the amounts of the reactants, from 1 to 50 equivalents of the compound represented by the formula (47) may be used per 1 equivalent of the compound represented by the formula (46).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide suchas dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions.

As the base, if used, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal hydroxide such as hydroxide, potassium hydroxide, calcium hydroxide or sodium acetate, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, an alkali metal amide such as lithium diidopropylamide, lithium diisopropylamide, lithium hexamethyldisilazane or sodium amide, an organic metal compound such as t-butyllithium, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, an organic base such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine or imidazole, 1,8-diazabicyclo[5,4,0]-7-undecene or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (46) or (47).

The reaction temperature may be set arbitrarily within the range of from −60° C. to the refluxing temperature of the reaction mixture, and the reaction time may be set arbitrarily within the range of from 5 minutes to 100 hours, though it depends on the concentrations of the reactants and the reaction temperature.

In general, the reaction is preferably carried out by using 1 equivalent of a compound represented by the formula (46) and a compound represented by the formula (47) in a solvent such as ethanol, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, chloroform or methylene chloride, if necessary by using from 1 to 3 equivalents of a base suchas sodium hydride, potassium t-butoxdie, potassium hydroxide, potassium carbonate, sodium acetate, triethylamine or pyrimidine per 1 equivalent of the compound represented by the formula (46) or (47) at 0-100° C. for 10 minutes to 24 hours.

Some of the amine compounds represented by the formula (47) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized from known compounds by known methods disclosed in the literature such as J. Am. Chem. Soc, 2011, vol. 133, p. 8704.

In Processes A, B, C, D, F and G, the reaction mixture obtained after the reaction is worked up by ordinary operations such as direct concentration, dissolution in an organic solvent followed by washing with water and concentration, or addition to ice-cold water followed by extraction with an organic solvent and concentration to obtain a compound of the present invention as intended. If purification is needed, it may be isolated or purified by a certain method such as recrystallization, column chromatography, thin layer chromatography and liquid chromatography.

The compound represented by the formula (13) used in Process B can be synthesized, for example, as follows.

A known substituted amine represented by the formula (19) [wherein R⁴, R⁵, R⁸ and X are the same as defined above] and a compound represented by the formula (20) [wherein k¹ and k² are hydrogen atoms, trichloromethyl groups, cyclohexyl groups, phenyl groups, p-cyanophenyl groups, ethoxycarbonyl groups or the like, and Boc is a t-butoxycarbonyl group are reacted, if necessary by using a solvent inert to the reaction, by a known method disclosed in the literature such as Tetrahedron Lett., 1989, vol. 39, p. 6845 to obtain a compound represented by the formula (13) [wherein R⁴, R⁵, R⁸ and X are the same as defined above].

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide such as dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

Some of the compounds represented by the formula (19) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized from known compounds by known methods disclosed in the literature such as Journal of Medicinal Chemistry, 2009, vol. 52, p. 3982, Chem. Commun., 2001, p. 1792, and Synthesis 2000, vol. 12, p. 1709.

The compound represented by the formula (20) used herein can be synthesized readily from a known compound in accordance with Journal of Medicinal Chemistry, 2009, vol. 52, p. 1471 [52(5), 1471-1476; 2009] or WO2008/073987.

The compound represented by the formula (13) used in Process B can be synthesized in accordance with J. Chem. Soc., Chem. Commun., 1986, p. 176, or J. Chem. Soc., Chem. Commun., 1983, p. 1040, for example, as follows.

An ethyl pivalate represented by the formula (22) and a phenyl Grignard reagent by the formula are reacted, if necessary by using a solvent inert to the reaction, the resulting alcohol compound represented by the formula (23) is halogenated, and the resulting halide compound represented by the formula (24) is reacted with hydrazine to obtain a hydrazine compound represented by the formula (25).

The resulting hydrazine compound represented by the formula (25) is reacted with a carbonyl compound represented by the formula (26), if necessary by using a solvent inert to the reaction, the resulting hydrazine compound represented by the formula (27) is reacted with a halide compound represented by the formula (28), if necessary in the presence of a base, if necessary by using a solvent inert to the reaction, and the resulting hydrazine compound represented by the formula (29) is reacted in the presence of an acid, if necessary by using a solvent inert to the reaction to obtain a hydrazine compound represented by the formula (30).

The resulting hydrazinecompound represented by the formula (30) is reacted in the presence of an acid, if necessary by using a solvent inert to the reaction to obtain a hydrazine compound represented by the formula (13).

As the solvent, if used, an aromatic hydrocarbon such as benzene, toluene or xylene, an aliphatic hydrocarbon such as hexane or heptane, an alicyclic hydrocarbon such as cyclohexane, an aromatic halohydrocarbon such as chlorobenzene or dichlorobenzene, an aliphatic halohydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene or tetrachloroethylene, an ether such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate or ethyl propionate, an amide suchas dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidone, an amine such as triethylamine, tributylamine or N,N-dimethylaniline, a pyridine such as pyridine or picoline, an alcohol such as methanol, ethanol or ethylene glycol, acetonitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-1-imidazolidinone, water or the like may, for example, be mentioned, though it may be any solvent that does not hinder the progress of the reaction without any particular restrictions. These solvents may be used alone or in combinations of two or more.

As the base, if used, an alkali metal hydride such as sodium hydride or potassium hydride, an alkali metal hydroxide such as hydroxide or potassium hydroxide, an alkali metal alkoxide such as sodium ethoxide or potassium t-butoxide, an alkali metal amide such as lithium diidopropylamide, lithium diisopropylamide, lithium hexamethyldisilazane or sodium amide, an organic metal compound such as t-butyllithium, an alkali metal carbonate such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, an organic base such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine or imidazole, 1,8-diazabicyclo[5,4,0]-7-undecene or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (27).

As the acid, if used, a mineral acid such as hydrochloric acid or sulfuric acid, a carboxylic acid such as formic acid, acetic acid, trifluoroacetic acid, mandelic acid or tartaric acid, a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid, benzensulfonic acid, trifluoromethanesulfonic acid or camphor sulfonic acid, phosphorus oxychloride, Amberlite IR-120 (type H) or the like may be used in an amount of from 1 to 10 equivalents per 1 equivalent of a compound represented by the formula (29) or (30).

The reaction temperature may be set arbitrarily within the range of from −60° C. to the refluxing temperature of the reaction mixture, and the reaction time may be set arbitrarily within the range of from 5 minutes to 100 hours, though it depends on the concentrations of the reactants and the reaction temperature.

Some of the compounds represented by the formula (22) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized by ordinary methods for synthesis of ester compounds disclosed in the literature.

Some of the compounds represented by the formula (26) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized by ordinary methods for synthesis of carbonyl compounds disclosed in the literature.

Some of the compounds represented by the formula (28) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized by ordinary methods for synthesis of halide compounds disclosed in the literature.

The compound represented by the formula (12) used in Process B can be synthesized in accordance with J. Am. Chem. Soc., 1958, vol. 80, p. 6562, for example, as follows.

Hydrazine and a carbonyl compound represented by the formula (26) are reacted, if necessary by using a solvent inert to the reaction, and the resulting hydrazine compound represented by the formula (31) is reacted with a Grignard reagent represented by the formula (32) to obtain a hydrazine compound represented by the formula (33).

The resulting hydrazine compound represented by the formula (33) is reacted in the presence of an acid, if necessary by using a solvent inert to the reaction to obtain a hydrazine compound represented by the formula (13).

Some of the compounds represented by the formula (26) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized by ordinary methods for synthesis of carbonyl compounds disclosed in the literature.

Some of the compounds represented by the formula (32) used herein are known compounds, and some of them are commercially available. The rest of them can be readily synthesized by ordinary methods for synthesis of Grignard reagents disclosed in the literature.

In each of these reactions, the reaction mixture is worked up by ordinary operations to obtain each intermediate used as a starting compound.

Each intermediate produced in these processes can be used for the reaction in the next step without isolation or purification.

As specific compounds of the present invention, for example, those shown in Tables 2 to 15 may be mentioned. However, the compounds merely exemplify the present invention, and the present invention is by no means restricted thereto.

In the Tables, Et denotes ethyl group, and similarly, n-Pr and Pr-n denote normal propyl group, i-Pr and Pr—I denote isopropyl group, c-Pr and Pr-c denote cyclopropyl group, n-Bu and Bu-n denote normal butyl group, s-Bu and Bu-s denote secondary butyl group, i-Bu and Bu—I denote isobutyl group, t-Bu and Bu-t denote t-butyl group, c-Bu and Bu-c denote cyclobutyl group, n-Pen and Pen-n denote normal pentyl group, c-Pen and Pen-c denote cyclopentyl group, n-Hex and Hex-n denote normal hexyl group, c-Hex and Hex-c denote cyclohexyl group, and Ph denotes phenyl group.

The aromatic heterocyclic rings represented by A001 to A044 in the Talbes have the following structures, respectively.

The aliphatic heterocyclic rings represented by A051 to A068 in the Talbes have the following structures, respectively.

The partially saturated heterocyclic rings represented by A101 to A107 in the Talbes have the following structures, respectively.

TABLE 2 The locants for the substituents R²¹ and R⁸¹ in the Table correspond to the positions indicated in the following structural formulae.

R²¹ R⁸¹ R³ R⁶ R⁷ H H H H H H 4-F H H H H 2-Cl H H H H 3-Cl H H H H 4-Cl H H H H 4-Cl CH₃ H H H 4-Cl CH₂Ph H H H 4-Cl C(O)Ph H H H 4-Cl C(O)OEt H H H 4-Cl H H CH₃ H 4-Cl CH₃ H CH₃ H 4-Cl H CH₃ CH₃ H 4-Br H H H H 4-I H H H H 2,4-Cl₂ H H H H 3,4-Cl₂ H H H H 4-NO₂ H H H H 4-CN H H H H 2-CH₃ H H H H 3-CH₃ H H H H 4-CH₃ H H H H 4-CH₃ CH₃ H H H 4-CH₃ CH₂Ph H H H 4-CH₃ C(O)Ph H H H 4-CH₃ C(O)OEt H H H 4-CH₃ H H CH₃ H 4-CH₃ CH₃ H CH₃ H 4-CH₃ H CH₃ CH₃ H 4-Et H H H H 4-n-Pr H H H H 4-c-Pr H H H H 4-i-Pr H H H H 4-n-Bu H H H H 4-c-Bu H H H H 4-i-Bu H H H H 4-t-Bu H H H H 4-t-Bu CH₃ H H H 4-t-Bu CH₂Ph H H H 4-t-Bu C(O)Ph H H H 4-t-Bu C(O)OEt H H H 4-t-Bu H H CH₃ H 4-t-Bu CH₃ H CH₃ H 4-t-Bu H CH₃ CH₃ H 4-n-Pen H H H H 4-c-Pen H H H H 4-n-Hex H H H H 4-n-Hex CH₃ H H H 4-n-Hex CH₂Ph H H H 4-n-Hex C(O)Ph H H H 4-n-Hex C(O)OEt H H H 4-n-Hex H H CH₃ H 4-n-Hex CH₃ H CH₃ H 4-n-Hex H CH₃ CH₃ H 4-c-Hex H H H H 4-n-C₇H₁₅ H H H H 4-n-C₈H₁₇ H H H H 4-n-C₉H₁₉ H H H H 4-n-C₁₀H₂₁ H H H H 2,4-(CH₃) H H H H 3,4-(CH₃)₂ H H H H 4-CF₃ H H H H 4-OH H H H H 2-OCH₃ H H H H 3-OCH₃ H H H H 4-OCH₃ H H H H 4-O-n-Hex H H H H 4-O-c-Hex H H H H 2,4-(OCH₃)₂ H H H H 3,4-(OCH₃)₂ H H H H 4-OCH₂OCH₃ H H H H 4-OC₂H₄OEt H H H H 4-OCF₃ H H H H 4-OPh H H H H 4-OCH₂Ph H H H H 4-C(CH₃)═NCH₃ H H H H 4-C(CH₃)═NPh H H H H 4-C(Ph)═NCH₃ H H H H 4-C(Ph)═NPh H H H H 4-C(CH₃)═NOCH₃ H H H H 4-C(CH₃)═NOPh H H H H 4-C(Ph)═NOCH₃ H H H H 4-C(Ph)═NOPh H H H H 4-C(O)CH₃ H H H H 4-C(O)CF₃ H H H H 4-C(O)Ph H H H H 4-C(O)OCH₃ H H H H 2-C(O)OEt H H H H 3-C(O)OEt H H H H 4-C(O)OEt H H H H 4-C(O)OPh H H H H 4-C(O)OCH₂Ph H H H H 4-C(O)OCH(CH₃)Ph H H H H 4-C(O)OC₂H₄Ph H H H H 4-SCH₃ H H H H 4-S(O)CH₃ H H H H 4-S(O)₂CH₃ H H H H 4-SPh H H H H 4-S(O)Ph H H H H 4-S(O)₂Ph H H H H 4-OS(O)₂CH₃ H H H H 4-OS(O)₂Ph H H H H 4-N(CH₃)₂ H H H H 4-N(CH₂Ph)₂ H H H H 4-N(CH₃)(CH₂Ph) H H H H 4-NHCH₃ H H H H 4-NH(CH₂Ph) H H H H 4-C(O)N(CH₃)₂ H H H H 4-C(O)N(CH₂Ph)₂ H H H H 4-C(O)N(CH₃)(CH₂Ph) H H H H 4-C(O)NHCH₃ H H H H 4-C(O)NH(CH₂Ph) H H H H 4-C(O)NH(CH(CH₃)Ph) H H H H 4-C(O)NH(C₂H₄Ph) H H H H 4-C(S)NH₂ H H H H 4-S(O)₂N(CH₃)₂ H H H H 4-S(O)₂N(CH₂Ph)₂ H H H H 4-S(O)₂N(CH₃)(CH₂Ph) H H H H 4-S(O)₂NHCH₃ H H H H 4-S(O)₂NHPh H H H H 4-S(O)₂NH(CH₂Ph) H H H H 4-S(O)₂NH{CH(CH₃)Ph} H H H H 4-S(O)₂NH(C₂H₄Ph) H H H H 4-Ph H H H H 4-Ph CH₃ H H H 4-Ph CH₂Ph H H H 4-Ph C(O)Ph H H H 4-Ph C(O)OEt H H H 4-Ph H H CH₃ H 4-Ph CH₃ H CH₃ H 4-Ph H CH₃ CH₃ 4-F H H H H 4-F 4-Cl H H H 4-F 4-Br H H H 4-F 4-CH₃ H H H 4-F 4-t-Bu H H H 4-F 4-n-Hex H H H 4-F 4-Ph H H H 2-Cl H H H H 2-Cl 4-Cl H H H 2-Cl 4-Br H H H 2-Cl 4-CH₃ H H H 2-Cl 4-t-Bu H H H 2-Cl 4-n-Hex H H H 2-Cl 4-Ph H H H 3-Cl H H H H 3-Cl 4-Cl H H H 3-Cl 4-Br H H H 3-Cl 4-CH₃ H H H 3-Cl 4-t-Bu H H H 3-Cl 4-n-Hex H H H 3-Cl 4-Ph H H H 4-Cl H H H H 4-Cl 4-Cl H H H 4-Cl 4-Br H H H 4-Cl 4-CH₃ H H H 4-Cl 4-t-Bu H H H 4-Cl 4-t-Bu CH₃ H H 4-Cl 4-n-Hex H H H 4-Cl 4-n-Hex CH₃ H H 4-Cl 4-n-Hex H H CH₃ 4-Cl 4-n-Hex H CH₃ CH₃ 4-Cl 4-Ph H H H 4-Cl 4-Ph CH₃ H H 4-Br H H H H 4-Br 4-Cl H H H 4-Br 4-Br H H H 4-Br 4-CH₃ H H H 4-Br 4-t-Bu H H H 4-Br 4-n-Hex H H H 4-Br 4-Ph H H H 3,4-Cl₂ H H H H 3,4-Cl₂ 4-Cl H H H 3,4-Cl₂ 4-Br H H H 3,4-Cl₂ 4-CH₃ H H H 3,4-Cl₂ 4-t-Bu H H H 3,4-Cl₂ 4-n-Hex H H H 3,4-Cl₂ 4-Ph H H H 4-NO₂ H H H H 4-NO₂ 4-Cl H H H 4-NO₂ 4-Br H H H 4-NO₂ 4-CH₃ H H H 4-NO₂ 4-t-Bu H H H 4-NO₂ 4-n-Hex H H H 4-NO₂ 4-Ph H H H 4-CN H H .H H 4-CN 4-Cl H H H 4-CN 4-Br H H H 4-CN 4-CH₃ H H H 4-CN 4-t-Bu H H H 4-CN 4-n-Hex H H H 4-CN 4-Ph H H H 2-CH₃ H H H H 2-CH₃ 4-Cl H H H 2-CH₃ 4-Br H H H 2-CH₃ 4-CH₃ H H H 2-CH₃ 4-t-Bu H H H 2-CH₃ 4-n-Hex H H H 2-CH₃ 4-Ph H H H 3-CH₃ H H H H 3-CH₃ 4-Cl H H H 3-CH₃ 4-Br H H H 3-CH₃ 4-CH₃ H H H 3-CH₃ 4-t-Bu H H H 3-CH₃ 4-n-Hex H H H 3-CH₃ 4-Ph H H H 4-CH₃ H H H H 4-CH₃ 4-Cl H H H 4-CH₃ 4-Br H H H 4-CH₃ 4-CH3 H H H 4-CH₃ 4-t-Bu H H H 4-CH₃ 4-t-Bu CH₃ H H 4-CH₃ 4-n-Hex H H H 4-CH₃ 4-n-Hex CH₃ H H 4-CH₃ 4-n-Hex H H CH₃ 4-CH₃ 4-n-Hex H CH₃ CH₃ 4-CH₃ 4-Ph H H H 4-CH₃ 4-Ph CH₃ H H 4-c-Pr H H H H 4-c-Pr 4-Cl H H H 4-c-Pr 4-Br H H H 4-c-Pr 4-CH₃ H H H 4-c-Pr 4-t-Bu H H H 4-c-Pr 4-n-Hex H H H 4-c-Pr 4-Ph H H H 4-i-Pr H H H H 4-i-Pr 4-Cl H H H 4-i-Pr 4-Br H H H 4-i-Pr 4-CH₃ H H H 4-i-Pr 4-t-Bu H H H 4-i-Pr 4-n-Hex H H H 4-i-Pr 4-Ph H H H 4-t-Bu H H H H 4-t-Bu 4-Cl H H H 4-t-Bu 4-Br H H H 4-t-Bu 4-CH₃ H H H 4-t-Bu 4-t-Bu H H H 4-t-Bu 4-t-Bu CH₃ H H 4-t-Bu 4-n-Hex H H H 4-t-Bu 4-n-Hex CH₃ H H 4-t-Bu 4-n-Hex H H CH₃ 4-t-Bu 4-n-Hex H CH₃ CH₃ 4-t-Bu 4-Ph H H H 4-t-Bu 4-Ph CH₃ H H 4-n-Hex H H H H 4-n-Hex H CH₃ H H 4-n-Hex H CH₂Ph H H 4-n-Hex H C(O)Ph H H 4-n-Hex H C(O)OEt H H 4-n-Hex H H H CH₃ 4-n-Hex H CH₃ H CH₃ 4-n-Hex H H CH₃ CH₃ 4-n-Hex 4-F H H H 4-n-Hex 2-Cl H H H 4-n-Hex 3-Cl H H H 4-n-Hex 4-Cl H H H 4-n-Hex 4-Cl CH₃ H H 4-n-Hex 4-Cl CH₂Ph H H 4-n-Hex 4-Cl C(O)Ph H H 4-n-Hex 4-Cl C(O)OEt H H 4-n-Hex 4-Cl H H CH₃ 4-n-Hex 4-Cl CH₃ H CH₃ 4-n-Hex 4-Cl H CH₃ CH₃ 4-n-Hex 4-Br H H H 4-n-Hex 4-I H H H 4-n-Hex 2,4-Cl₂ H H H 4-n-Hex 3,4-Cl₂ H H H 4-n-Hex 4-NO₂ H H H 4-n-Hex 4-CN H H H 4-n-Hex 2-CH₃ H H H 4-n-Hex 3-CH₃ H H H 4-n-Hex 4-CH₃ H H H 4-n-Hex 4-CH₃ CH₃ H H 4-n-Hex 4-CH₃ CH₂Ph H H 4-n-Hex 4-CH₃ C(O)Ph H H 4-n-Hex 4-CH₃ C(O)OEt H H 4-n-Hex 4-CH₃ H H CH₃ 4-n-Hex 4-CH₃ CH₃ H CH₃ 4-n-Hex 4-CH₃ H CH₃ CH₃ 4-n-Hex 4-Et H H H 4-n-Hex 4-n-Pr H H H 4-n-Hex 4-c-Pr H H H 4-n-Hex 4-i-Pr H H H 4-n-Hex 4-n-Bu H H H 4-n-Hex 4-c-Bu H H H 4-n-Hex 4-i-Bu H H H 4-n-Hex 4-t-Bu H H H 4-n-Hex 4-t-Bu CH₃ H H 4-n-Hex 4-t-Bu CH₂Ph H H 4-n-Hex 4-t-Bu C(O)Ph H H 4-n-Hex 4-t-Bu C(O)0Et H H 4-n-Hex 4-t-Bu H H CH₃ 4-n-Hex 4-t-Bu CH₃ H CH₃ 4-n-Hex 4-t-Bu H CH₃ CH₃ 4-n-Hex 4-n-Pen H H H 4-n-Hex 4-c-Pen H H H 4-n-Hex 4-n-Hex H H H 4-n-Hex 4-n-Hex CH₃ H H 4-n-Hex 4-n-Hex CH₂Ph H H 4-n-Hex 4-n-Hex C(O)Ph H H 4-n-Hex 4-n-Hex C(O)OEt H H 4-n-Hex 4-n-Hex H H CH₃ 4-n-Hex 4-n-Hex CH₃ H CH₃ 4-n-Hex 4-n-Hex H CH₃ CH₃ 4-n-Hex 4-c-Hex H H H 4-n-Hex 4-n-C₇H₁₅ H H H 4-n-Hex 4-n-C₈H₁₇ H H H 4-n-Hex 4-n-C₉H₁₉ H H H 4-n-Hex 4-n-C₁₀H₂₁ H H H 4-n-Hex 2,4-(CH₃) H H H 4-n-Hex 3,4-(CH₃)₂ H H H 4-n-Hex 4-CF₃ H H H 4-n-Hex 4-OH H H H 4-n-Hex 2-OCH₃ H H H 4-n-Hex 3-OCH₃ H H H 4-n-Hex 4-OCH₃ H H H 4-n-Hex 4-O-n-Hex H H H 4-n-Hex 4-O-c-Hex H H H 4-n-Hex 2,4-(OCH₃)₂ H H H 4-n-Hex 3,4-(OCH₃)₂ H H H 4-n-Hex 4-OCH₂OCH₃ H H H 4-n-Hex 4-OC₂H₄OEt H H H 4-n-Hex 4-OCF₃ H H H 4-n-Hex 4-OPh H H H 4-n-Hex 4-OCH₂Ph H H H 4-n-Hex 4-C(CH₃)═NCH₃ H H H 4-n-Hex 4-C(CH₃)═NPh H H H 4-n-Hex 4-C(Ph)═NCH₃ H H H 4-n-Hex 4-C(Ph)═NPh H H H 4-n-Hex 4-C(CH₃)═NOCH₃ H H H 4-n-Hex 4-C(CH₃)═NOPh H H H 4-n-Hex 4-C(Ph)═NOCH₃ H H H 4-n-Hex 4-C(Ph)═NOPh H H H 4-n-Hex 4-C(O)CH₃ H H H 4-n-Hex 4-C(O)CF₃ H H H 4-n-Hex 4-C(O)Ph H H H 4-n-Hex 4-C(O)OCH₃ H H H 4-n-Hex 2-C(O)OEt H H H 4-n-Hex 3-C(O)OEt H H H 4-n-Hex 4-C(O)OEt H H H 4-n-Hex 4-C(O)OPh H H H 4-n-Hex 4-C(O)OCH₂Ph H H H 4-n-Hex 4-C(O)OCH(CH₃)Ph H H H 4-n-Hex 4-C(O)OC₂H₄Ph H H H 4-n-Hex 4-SCH₃ H H H 4-n-Hex 4-S(O)CH₃ H H H 4-n-Hex 4-S(O)₂CH₃ H H H 4-n-Hex 4-SPh H H H 4-n-Hex 4-S(O)Ph H H H 4-n-Hex 4-S(O)₂Ph H H H 4-n-Hex 4-OS(O)₂CH₃ H H H 4-n-Hex 4-OS(O)₂Ph H H H 4-n-Hex 4-N(CH₃)₂ H H H 4-n-Hex 4-N(CH₂Ph)₂ H H H 4-n-Hex 4-N(CH₃)(CH₂Ph) H H H 4-n-Hex 4-NHCH₃ H H H 4-n-Hex 4-NH(CH₂Ph) H H H 4-n-Hex 4-C(O)N(CH₃)₂ H H H 4-n-Hex 4-C(O)N(CH₂Ph)₂ H H H 4-n-Hex 4-C(O)N(CH₃)(CH₂Ph) H H H 4-n-Hex 4-C(O)NHCH₃ H H H 4-n-Hex 4-C(O)NH(CH₂Ph) H H H 4-n-Hex 4-C(O)NH{CH(CH₃)Ph} H H H 4-n-Hex 4-C(O)NH(C₂H₄Ph) H H H 4-n-Hex 4-C(S)NH₂ H H H 4-n-Hex 4-S(O)₂N(CH₃)₂ H H H 4-n-Hex 4-S(O)₂N(CH₂Ph)₂ H H H 4-n-Hex 4-S(O)₂N(CH₃)(CH₂Ph) H H H 4-n-Hex 4-S(O)₂NHCH₃ H H H 4-n-Hex 4-S(O)₂NHPh H H H 4-n-Hex 4-S(O)₂NH(CH₂Ph) H H H 4-n-Hex 4-S(O)₂NH{CH(CH₃)Ph} H H H 4-n-Hex 4-S(O)₂NH(C₂H₄Ph) H H H 4-n-Hex 4-Ph H H H 4-n-Hex 4-Ph CH₃ H H 4-n-Hex 4-Ph CH₂Ph H H 4-n-Hex 4-Ph C(O)Ph H H 4-n-Hex 4-Ph C(O)OEt H H 4-n-Hex 4-Ph H H CH₃ 4-n-Hex 4-Ph CH₃ H CH₃ 4-n-Hex 4-Ph H CH₃ CH₃ 4-c-Hex H H H H 4-c-Hex 4-Cl H H H 4-c-Hex 4-Br H H H 4-c-Hex 4-CH₃ H H H 4-c-Hex 4-t-Bu H H H 4-c-Hex 4-t-Bu CH₃ H H 4-c-Hex 4-n-Hex H H H 4-c-Hex 4-n-Hex CH₃ H H 4-c-Hex 4-n-Hex H H CH₃ 4-c-Hex 4-n-Hex H CH₃ CH₃ 4-c-Hex 4-Ph H H H 4-c-Hex 4-Ph CH₃ H H 3,4-(CH₃)₂ H H H H 3,4-(CH₃)₂ 4-Cl H H H 3,4-(CH₃)₂ 4-Br H H H 3,4-(CH₃)₂ 4-CH₃ H H H 3,4-(CH₃)₂ 4-t-Bu H H H 3,4-(CH₃)₂ 4-n-Hex H H H 3,4-(CH₃)₂ 4-Ph H H H 2,4-(t-Bu)₂ H H H H 2,4-(t-Bu)₂ 4-Cl H H H 2,4-(t-Bu)₂ 4-Br H H H 2,4-(t-Bu)₂ 4-CH₃ H H H 2,4-(t-Bu)₂ 4-t-Bu H H H 2,4-(t-Bu)₂ 4-n-Hex H H H 2,4-(t-Bu)₂ 4-Ph H H H 4-CF₃ H H H H 4-CF₃ 4-Cl H H H 4-CF₃ 4-Br H H H 4-CF₃ 4-CH₃ H H H 4-CF₃ 4-t-Bu H H H 4-CF₃ 4-n-Hex H H H 4-CF₃ 4-Ph H H H 4-OH H H H H 4-OH 4-Cl H H H 4-OH 4-Br H H H 4-OH 4-CH₃ H H H 4-OH 4-t-Bu H H H 4-OH 4-n-Hex H H H 4-OH 4-Ph H H H 4-OCH₃ H H H H 4-OCH₃ 4-Cl H H H 4-OCH₃ 4-Br H H H 4-OCH₃ 4-CH₃ H H H 4-OCH₃ 4-t-Bu H H H 4-OCH₃ 4-n-Hex H H H 4-OCH₃ 4-Ph H H H 4-O-i-Pr H H H H 4-O-i-Pr 4-Cl H H H 4-O-i-Pr 4-Br H H H 4-O-i-Pr 4-CH₃ H H H 4-O-i-Pr 4-t-Bu H H H 4-O-i-Pr 4-n-Hex H H H 4-O-i-Pr 4-Ph H H H 4-O-n-Hex H H H H 4-O-n-Hex 4-Cl H H H 4-O-n-Hex 4-Br H H H 4-O-n-Hex 4-CH₃ H H H 4-O-n-Hex 4-t-Bu H H H 4-O-n-Hex 4-n-Hex H H H 4-O-n-Hex 4-Ph H H H 3,4-(OCH₃)₂ H H H H 3,4-(OCH₃)₂ 4-Cl H H H 3,4-(OCH₃)₂ 4-Br H H H 3,4-(OCH₃)₂ 4-CH₃ H H H 3,4-(OCH₃)₂ 4-t-Bu H H H 3,4-(OCH₃)₂ 4-n-Hex H H H 3,4-(OCH₃)₂ 4-Ph H H H 4-OC₂H₄OEt H H H H 4-OC₂H₄OEt 4-Cl H H H 4-OC₂H₄OEt 4-Br H H H 4-OC₂H₄OEt 4-CH₃ H H H 4-OC₂H₄OEt 4-t-Bu H H H 4-OC₂H₄OEt 4-n-Hex H H H 4-OC₂H₄OEt 4-Ph H H H 4-OPh H H H H 4-OPh 4-Cl H H H 4-OPh 4-Br H H H 4-OPh 4-CH₃ H H H 4-OPh 4-t-Bu H H H 4-OPh 4-n-Hex H H H 4-OPh 4-Ph H H H 4-OCH₂Ph H H H H 4-OCH₂Ph 4-Cl H H H 4-OCH₂Ph 4-Br H H H 4-OCH₂Ph 4-CH₃ H H H 4-OCH₂Ph 4-t-Bu H H H 4-OCH₂Ph 4-n-Hex H H H 4-OCH₂Ph 4-Ph H H H 4-Ph H H H H 4-Ph 4-Cl H H H 4-Ph 4-Br H H H 4-Ph 4-CH₃ H H H 4-Ph 4-t-Bu H H H 4-Ph 4-t-Bu CH₃ H H 4-Ph 4-n-Hex H H H 4-Ph 4-n-Hex CH₃ H H 4-Ph 4-n-Hex H H CH₃ 4-Ph 4-n-Hex H CH₃ CH₃ 4-Ph 4-Ph H H H 4-Ph 4-Ph CH₃ H H

TABLE 3 The locants for the substituent R⁸¹ in the Table correspond to the positions indicated in the following structural formulae.

R² (Z)m R⁸¹ R³ R⁶ R⁷ H — H H H H H — 4-CH₃ H H H F — H H H H CH₃ — H H H H Et — H H H H n-Pr — H H H H c-Pr — H H H H i-Pr — H H H H n-Bu — H H H H c-Bu — H H H H i-Bu — H H H H t-Bu — H H H H n-Pen — H H H H c-Pen — H H H H n-Hex — H H H H c-Hex — H H H H n-C₇H₁₅ — H H H H n-C₈H₁₇ — H H H H n-C₉H₁₉ — H H H H n-C₁₀H₂ — H H H H CF₃ — H H H H C(Ph)═NCH₃ — H H H H C(CH₃)═NPh — H H H H C(Ph)═NOCH₃ — H H H H C(O)CH₃ — H H H H C(O)Et — H H H H C(O)CF₃ — H H H H C(O)Ph — H H H H C(O)Ph — 4-Cl H H H C(O)Ph — 4-Cl H H CH₃ C(O)Ph — 4-CH₃ H H H C(O)Ph — 4-CH₃ CH₃ H H C(O)Ph — 4-CH₃ CH₂Ph H H C(O)Ph — 4-CH₃ C(O)Ph H H C(O)Ph — 4-CH₃ C(O)OEt H H C(O)Ph — 4-CH₃ H H CH₃ C(O)Ph — 4-CH₃ H CH₃ CH₃ C(O)Ph — 4-t-Bu H H H C(O)Ph — 4-t-Bu H H CH₃ C(O)Ph — 4-n-hex H H H C(O)Ph — 4-n-hex H H CH₃ C(O)Ph — 4-OCH₃ H H H C(O)Ph — 4-OCH₃ H H CH₃ C(O)Ph — 4-Ph H H H C(O)Ph — 4-Ph H H CH₃ C(O)CH₂Ph — H H H H C(O)CH(CH₃)Ph — H H H H C(O)C₂H₄Ph — H H H H C(O)OCH₃ — H H H H C(O)OEt — H H H H C(O)OEt — 4-Cl H H H C(O)OEt — 4-Cl H H CH₃ C(O)OEt — 4-CH, H H H C(O)OEt — 4-CH₃ CH₃ H H C(O)OEt — 4-CH₃ CH₂Ph H H C(O)OEt — 4-CH₃ C(O)Ph H H C(O)OEt — 4-CH₃ C(O)OEt H H C(O)OEt — 4-CH₃ H H CH₃ C(O)OEt — 4-CH₃ H CH₃ CH₃ C(O)OEt — 4-t-Bu H H H C(O)OEt — 4-t-Bu H H CH₃ C(O)OEt — 4-n-hex H H H C(O)OEt — 4-n-hex H H CH₃ C(O)OEt — 4-OCH₃ H H H C(O)OEt — 4-OCH₃ H H CH₃ C(O)OEt — 4-Ph H H H C(O)OEt — 4-Ph H H CH₃ C(O)OPh — H H H H C(O)OCH₂Ph — H H H H C(O)OCH(CH₃)Ph — H H H H C(O)OC₂H₄Ph — H H H H C(O)N(CH₃)2 — H H H H C(O)NHCH₃ — H H H H C(O)NH(CH₂Ph) — H H H H CH₂Ph — H H H H CH₂(4-Cl-Ph) — H H H H A001 H H H H H A001 3-n-Bu H H H H A002 H H H H H A002 2-Cl H H H H A003 H H H H H A004 H H H H H A005 H H H H H A005 H 4-Cl H H H A005 H 4-Cl H H CH₃ A005 H 4-CH₃ H H H A005 H 4-CH₃ CH₃ H H A005 H 4-CH₃ CH₂Ph H H A005 H 4-CH₃ C(O)Ph H H A005 H 4-CH₃ C(O)OEt H H A005 H 4-CH₃ H H CH₃ A005 H 4-CH₃ H CH₃ CH₃ A005 H 4-t-Bu H H H A005 H 4-t-Bu H H CH₃ A005 H 4-n-hex H H H A005 H 4-n-hex H H CH₃ A005 H 4-OCH₃ H H H A005 H 4-OCH₃ H H CH₃ A005 H 4-Ph H H H A005 H 4-Ph H H CH₃ A005 2,5-(CH₃)₂ H H H H A005 2,5-Cl₂ H H H H A005 2-Br H H H H A006 H H H H H A006 H 4-Cl H H H A006 H 4-Cl H H CH₃ A006 H 4-CH₃ H H H A006 H 4-CH₃ CH₃ H H A006 H 4-CH₃ CH₂Ph H H A006 H 4-CH₃ C(O)Ph H H A006 H 4-CH₃ C(O)OEt H H A006 H 4-CH₃ H H CH₃ A006 H 4-CH₃ H CH3 CH₃ A006 H 4-t-Bu H H H A006 H 4-t-Bu H H CH₃ A006 H 4-n-hex H H H A006 H 4-n-hex H H CH₃ A006 H 4-OCH₃ H H H A006 H 4-OCH₃ H H CH₃ A006 H 4-Ph H H H A006 H 4-Ph H H CH₃ A006 3-CH₃ H H H H A006 5-CH₃ H H H H A006 3-Cl H H H H A006 5-Et H H H H A006 5-Cl H H H H A006 5-Br H H H H A006 3-Br H H H H A006 4-Br H H H H A006 5-NO₂ H H H H A007 H H H H H A007 5-CH₃ H H H H A007 3-CH₃ H H H H A007 5-Br H H H H A007 5-NO₂ H H H H A007 5-Ph H H H H A008 5-CH₃ H H H H A009 5-CH₃ H H H H A010 3,5-(CH₃)₂ H H H H A010 3,5-Cl₂ H H H H A011 3,5-(CH₃)₂ H H H H A011 3,5-Cl₂ H H H H A012 3-CH₃ H H H H A012 3-CH₃ H H H H A012 3-Cl H H H H A013 3-CH₃ H H H H A013 3-CH₃ H H H H A013 3-Cl H H H H A014 H H H H H A014 H 4-Cl H H H A014 H 4-Cl H H CH₃ A014 H 4-CH₃ H H H A014 H 4-CH₃ CH₃ H H A014 H 4-CH₃ CH₂Ph H H A014 H 4-CH₃ C(O)Ph H H A014 H 4-CH₃ C(O)OEt H H A014 H 4-CH₃ H H CH₃ A014 H 4-CH₃ H CH₃ CH₃ A014 H 4-t-Bu H H H A014 H 4-t-Bu H H CH₃ A014 H 4-n-hex H H H A014 H 4-n-hex H H CH₃ A014 H 4-OCH₃ H H H A014 H 4-OCH₃ H H CH₃ A014 H 4-Ph H H H A014 H 4-Ph H H CH₃ A015 H H H H H A016 2,4-(CH₃)₂ H H H H A016 2,4-(CH₃)₂ 4-Cl H H H A016 2,4-(CH₃)₂ 4-Cl H H CH₃ A016 2,4-(CH₃)₂ 4-CH₃ H H H A016 2,4-(CH₃)₂ 4-CH₃ CH₃ H H A016 2,4-(CH₃)₂ 4-CH₃ CH₂Ph H H A016 2,4-(CH₃)₂ 4-CH₃ C(O)Ph H H A016 2,4-(CH₃)₂ 4-CH₃ C(O)OEt H H A016 2,4-(CH₃)₂ 4-CH₃ H H CH₃ A016 2,4-(CH₃)₂ 4-CH₃ H CH₃ CH₃ A016 2,4-(CH₃)₂ 4-t-Bu H H H A016 2,4-(CH₃)₂ 4-t-Bu H H CH₃ A016 2,4-(CH₃)₂ 4-n-hex H H H A016 2,4-(CH₃)₂ 4-n-hex H H CH₃ A016 2,4-(CH₃)₂ 4-OCH₃ H H H A016 2,4-(CH₃)₂ 4-OCH₃ H H CH₃ A016 2,4-(CH₃)₂ 4-Ph H H H A016 2,4-(CH₃)₂ 4-Ph H H CH₃ A017 2,4-(CH₃)₂ H H H H A018 H H H H H A018 3-CH₃ H H H H A019 3-Ph, 5-CH₃ H H H H A019 3,5-(CH₃)₂ H H H H A020 5-CH₃ H H H H A021 4-CH₃ H H H H A022 H H H H H A023 2,4-(CH₃)₂ H H H H A024 2-(4-pyridil) H H H H A025 H H H H H A026 H H H H H A026 4-CH₃ H H H H A027 H H H H H A027 4-CH₃ H H H H A028 H H H H H A029 H H H H H A030 H H H H H A031 H H H H H A032 H H H H H A033 H H H H H A034 H H H H H A034 3,6-Cl₂ H H H H A035 H H H H H A036 H H H H H A036 H 4-Cl H H H A036 H 4-Cl H H CH₃ A036 H 4-CH₃ H H H A036 H 4-CH₃ CH₃ H H A036 H 4-CH₃ CH₂Ph H H A036 H 4-CH₃ C(O)Ph H H A036 H 4-CH₃ C(O)OEt H H A036 H 4-CH₃ H H CH₃ A036 H 4-CH₃ H CH₃ CH, A036 H 4-t-Bu H H H A036 H 4-t-Bu H H CH₃ A036 H 4-n-hex H H H A036 H 4-n-hex H H CH₃ A036 H 4-OCH₃ H H H A036 H 4-OCH₃ H H CH₃ A036 H 4-Ph H H H A036 H 4-Ph H H CH₃ A037 H H H H H A037 H 4-Cl H H H A037 H 4-Cl H H CH₃ A037 H 4-CH₃ H H H A037 H 4-CH₃ CH₃ H H A037 H 4-CH₃ CH₂Ph H H A037 H 4-CH₃ C(O)Ph H H A037 H 4-CH₃ C(O)OEt H H A037 H 4-CH₃ H H CH₃ A037 H 4-CH₃ H CH₃ CH₃ A037 H 4-t-Bu H H H A037 H 4-t-Bu H H CH₃ A037 H 4-n-hex H H H A037 H 4-n-hex H H CH₃ A037 H 4-OCH₃ H H H A037 H 4-OCH₃ H H CH₃ A037 H 4-Ph H H H A037 H 4-Ph H H CH₃ A037 6-OCH₃ H H H H A037 6-Br H H H H A038 H H H H H A038 H 4-Cl H H H A038 H 4-Cl H H CH₃ A038 H 4-CH₃ H H H A038 H 4-CH₃ CH₃ H H A038 H 4-CH₃ CH₂Ph H H A038 H 4-CH₃ C(O)Ph H H A038 H 4-CH₃ C(O)OEt H H A038 H 4-CH₃ H H CH₃ A038 H 4-CH₃ H CH₃ CH₃ A038 H 4-t-Bu H H H A038 H 4-t-Bu H H CH₃ A038 H 4-n-hex H H H A038 H 4-n-hex H H CH₃ A038 H 4-OCH₃ H H H A038 H 4-OCH₃ H H CH₃ A038 H 4-Ph H H H A038 H 4-Ph H H CH₃ A038 2-OCH₃ H H H H A038 4-OCH₃ H H H H A038 4-F H H H H A039 H H H H H A039 3-CH₃ H H H H A039 7-OCH₃ H H H H A040 H H H H H A041 H H H H H A041 H 4-Cl H H H A041 H 4-Cl H H CH₃ A041 H 4-CH₃ H H H A041 H 4-CH₃ CH₃ H H A041 H 4-CH₃ CH₂Ph H H A041 H 4-CH₃ C(O)Ph H H A041 H 4-CH₃ C(O)OEt H H A041 H 4-CH₃ H H CH₃ A041 H 4-CH₃ H CH₃ CH₃ A041 H 4-t-Bu H H H A041 H 4-t-Bu H H CH₃ A041 H 4-n-hex H H H A041 H 4-n-hex H H CH₃ A041 H 4-OCH₃ H H H A041 H 4-OCH₃ H H CH₃ A041 H 4-Ph H H H A041 H 4-Ph H H CH₃ A041 6-NO₂ H H H H A041 6-Br H H H H A042 H H H H H A042 H 4-Cl H H H A042 H 4-Cl H H CH₃ A042 H 4-CH₃ H H H A042 H 4-CH₃ CH₃ H H A042 H 4-CH₃ CH₂Ph H H A042 H 4-CH₃ C(O)Ph H H A042 H 4-CH₃ C(O)OEt H H A042 H 4-CH₃ H H CH₃ A042 H 4-CH₃ H CH₃ CH₃ A042 H 4-t-Bu H H H A042 H 4-t-Bu H H CH₃ A042 H 4-n-hex H H H A042 H 4-n-hex H H CH₃ A042 H 4-OCH₃ H H H A042 H 4-OCH₃ H H CH₃ A042 H 4-Ph H H H A042 H 4-Ph H H CH₃ A042 5-Br H H H H A043 H H H H H A044 H H H H H A051 — H H H H A052 — H H H H A053 — H H H H A054 — H H H H A055 — H H H H A056 — H H H H A057 — H H H H A058 — H H H H A059 — H H H H A060 — H H H H A061 — H H H H A062 — H H H H A063 — H H H H A064 — H H H H A065 — H H H H A066 — H H H H A067 — H H H H A068 — H H H H A101 — H H H H A102 — H H H H A103 — H H H H A104 — H H H H A105 — H H H H A106 — H H H H A107 — H H H H

TABLE 4 The locants for the substituent R²¹ herein correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R²¹ R⁸ (Z)m R³ R⁶ R⁷ H c-Pr — H H H 4-Cl c-Pr — H H H 4-Cl c-Pr — H H CH₃ 4-CH₃ c-Pr — H H H 4-CH₃ c-Pr — CH₃ H H 4-CH₃ c-Pr — CH₂Ph H H 4-CH₃ c-Pr — C(O)Ph H H 4-CH₃ c-Pr — C(O)OEt H H 4-CH₃ c-Pr — H H CH₃ 4-CH₃ c-Pr — H CH, CH₃ 4-t-Bu c-Pr — H H H 4-t-Bu c-Pr — H H CH₃ 4-n-hex c-Pr — H H H 4-n-hex c-Pr — CH₃ H H 4-n-hex c-Pr — CH₂Ph H H 4-n-hex c-Pr — C(O)Ph H H 4-n-hex c-Pr — C(O)OEt H H 4-n-hex c-Pr — H H CH₃ 4-n-hex c-Pr — H CH₃ CH₃ 4-OCH₃ c-Pr — H H H 4-OCH₃ c-Pr — H H CH₃ 4-Ph c-Pr — H H H 4-Ph c-Pr — H H CH₃ H c-Bu — H H H H c-Pen — H H H H c-Hex — H H H 4-Cl c-Hex — H H H 4-Cl c-Hex — H H CH₃ 4-CH₃ c-Hex — H H H 4-CH₃ c-Hex — CH₃ H H 4-CH₃ c-Hex — CH₂Ph H H 4-CH₃ c-Hex — C(O)Ph H H 4-CH₃ c-Hex — C(O)OEt H H 4-CH₃ c-Hex — H H CH₃ 4-CH₃ c-Hex — H CH₃ CH₃ 4-t-Bu c-Hex — H H H 4-t-Bu c-Hex — H H CH₃ 4-n-hex c-Hex — H H H 4-n-hex c-Hex — CH₃ H H 4-n-hex c-Hex — CH₂Ph H H 4-n-hex c-Hex — C(O)Ph H H 4-n-hex c-Hex — C(O)OEt H H 4-n-hex c-Hex — H H CH₃ 4-n-hex c-Hex — H CH₃ CH₃ 4-OCH₃ c-Hex — H H H 4-OCH₃ c-Hex — H H CH₃ 4-Ph c-Hex — H H H 4-Ph c-Hex — H H CH₃ H c-C₇H₁₅ — H H H H c-C₈H₁₇ — H H H H bicyclo[2.2.1]heptan-2-y1 — H H H H 1-adamantyl — H H H H 2-adamantyl — H H H H A001 H H H H H A001 3-n-Bu H H H H A002 H H H H H A002 2-Cl H H H H A003 H H H H H A004 H H H H H A005 H H H H 4-Cl A005 H H H H 4-Cl A005 H H H CH₃ 4-CH₃ A005 H H H H 4-CH₃ A005 H CH₃ H H 4-CH₃ A005 H CH₂Ph H H 4-CH₃ A005 H C(O)Ph H H 4-CH₃ A005 H C(O)OEt H H 4-CH₃ A005 H H H CH₃ 4-CH₃ A005 H H CH₃ CH₃ 4-t-Bu A005 H H H H 4-t-Bu A005 H H H CH₃ 4-n-hex A005 H H H H 4-n-hex A005 H CH₃ H H 4-n-hex A005 H CH₂Ph H H 4-n-hex A005 H C(O)Ph H H 4-n-hex A005 H C(O)OEt H H 4-n-hex A005 H H H CH₃ 4-n-hex A005 H H CH₃ CH₃ 4-OCH₃ A005 H H H H 4-OCH₃ A005 H H H CH₃ 4-Ph A005 H H H H 4-Ph A005 H H H CH₃ H A005 2,5-(CH₃)₂ H H H H A005 2,5-Cl₂ H H H H A005 2-Br H H H H A006 H H H H 4-Cl A006 H H H H 4-Cl A006 H H H CH₃ 4-CH₃ A006 H H H H 4-CH₃ A006 H CH₃ H H 4-CH₃ A006 H CH₂Ph H H 4-CH₃ A006 H C(O)Ph H H 4-CH₃ A006 H C(O)OEt H H 4-CH₃ A006 H H H CH₃ 4-CH₃ A006 H H CH₃ CH₃ 4-t-Bu A006 H H H H 4-t-Bu A006 H H H CH₃ 4-n-hex A006 H H H H 4-n-hex A006 H CH₃ H H 4-n-hex A006 H CH₂Ph H H 4-n-hex A006 H C(O)Ph H H 4-n-hex A006 H C(O)OEt H H 4-n-hex A006 H H H CH₃ 4-n-hex A006 H H CH₃ CH₃ 4-OCH₃ A006 H H H H 4-OCH₃ A006 H H H CH₃ 4-Ph A006 H H H H 4-Ph A006 H H H CH₃ H A006 3-CH₃ H H H H A006 5-CH₃ H H H H A006 3-Cl H H H H A006 5-Et H H H H A006 5-Cl H H H H A006 5-Br H H H H A006 3-Br H H H H A006 4-Br H H H H A006 5-NO₂ H H H H A007 H H H H H A007 5-CH₃ H H H H A007 3-CH₃ H H H H A007 5-Br H H H H A007 5-NO₂ H H H H A007 5-Ph H H H H A008 5-CH₃ H H H H A009 5-CH₃ H H H H A010 3,5-(CH₃)₂ H H H H A010 3,5-Cl₂ H H H H A011 3,5-(CH₃)₂ H H H H A011 3,5-Cl₂ H H H H A012 3-CH₃ H H H H A012 3-Me H H H H A012 3-Cl H H H H A013 3-CH₃ H H H H A013 3-Me H H H H A013 3-Cl H H H H A014 H H H H 4-Cl A014 H H H H 4-Cl A014 H H H CH₃ 4-CH₃ A014 H H H H 4-CH₃ A014 H CH₃ H H 4-CH₃ A014 H CH₂Ph H H 4-CH₃ A014 H C(O)Ph H H 4-CH₃ A014 H C(O)OEt H H 4-CH₃ A014 H H H CH₃ 4-CH₃ A014 H H CH₃ CH₃ 4-t-Bu A014 H H H H 4-t-Bu A014 H H H CH₃ 4-n-hex A014 H H H H 4-n-hex A014 H H H CH₃ 4-OCH₃ A014 H H H H 4-OCH₃ A014 H H H CH₃ 4-Ph A014 H H H H 4-Ph A014 H H H CH₃ H A015 H H H H H A016 2,4-(CH₃)₂ H H H 4-Cl A016 2,4-(CH₃)₂ H H H 4-Cl A016 2,4-(CH₃)₂ H H CH₃ 4-CH₃ A016 2,4-(CH₃)₂ H H H 4-CH₃ A016 2,4-(CH₃)₂ CH₃ H H 4-CH₃ A016 2,4-(CH₃)₂ CH₂Ph H H 4-CH₃ A016 2,4-(CH₃)₂ C(O)Ph H H 4-CH₃ A016 2,4-(CH₃)₂ C(O)OEt H H 4-CH₃ A016 2,4-(CH₃)₂ H H CH₃ 4-CH₃ A016 2,4-(CH₃)₂ H CH₃ CH₃ 4-t-Bu A016 2,4-(CH₃)₂ H H H 4-t-Bu A016 2,4-(CH₃)₂ H H CH₃ 4-n-hex A016 2,4-(CH₃)₂ H H H 4-n-hex A016 2,4-(CH₃)₂ H H CH₃ 4-OCH₃ A016 2,4-(CH₃)₂ H H H 4-OCH₃ A016 2,4-(CH₃)₂ H H CH₃ 4-Ph A016 2,4-(CH₃)₂ H H H 4-Ph A016 2,4-(CH₃)₂ H H CH₃ H A017 2,4-(CH₃)₂ H H H H A018 H H H H H A018 3-CH₃ H H H H A019 3-Ph, 5-CH₃ H H H H A019 3,5-(CH₃)₂ H H H H A020 5-CH₃ H H H H A021 4-CH₃ H H H H A022 H H H H H A023 2,4-(CH₃)₂ H H H H A024 2-(4-pyridil) H H H H A025 H H H H H A026 H H H H H A026 4-CH₃ H H H H A027 H H H H H A027 4-CH₃ H H H H A028 H H H H H A029 H H H H H A030 H H H H H A031 H H H H H A032 H H H H H A033 H H H H H A034 H H H H H A034 3,6-Cl₂ H H H H A035 H H H H H A036 H H H H H A037 H H H H 4-Cl A037 H H H H 4-Cl A037 H H H CH₃ 4-CH₃ A037 H H H H 4-CH₃ A037 H CH₃ H H 4-CH₃ A037 H CH₂Ph H H 4-CH₃ A037 H C(O)Ph H H 4-CH₃ A037 H C(O)OEt H H 4-CH₃ A037 H H H CH₃ 4-CH₃ A037 H H CH₃ CH₃ 4-t-Bu A037 H H H H 4-t-Bu A037 H H H CH₃ 4-n-hex A037 H H H H 4-n-hex A037 H CH₃ H H 4-n-hex A037 H CH₂Ph H H 4-n-hex A037 H C(O)Ph H H 4-n-hex A037 H C(O)OEt H H 4-n-hex A037 H H H CH₃ 4-n-hex A037 H H CH₃ CH₃ 4-OCH₃ A037 H H H H 4-OCH₃ A037 H H H CH₃ 4-Ph A037 H H H H 4-Ph A037 H H H CH₃ H A037 6-OCH₃ H H H H A037 6-Br H H H H A038 H H H H 4-Cl A038 H H H H 4-Cl A038 H H H CH₃ 4-CH₃ A038 H H H H 4-CH₃ A038 H CH₃ H H 4-CH₃ A038 H CH₂Ph H H 4-CH₃ A038 H C(O)Ph H H 4-CH₃ A038 H C(O)OEt H H 4-CH₃ A038 H H H CH₃ 4-CH₃ A038 H H CH₃ CH₃ 4-t-Bu A038 H H H H 4-t-Bu A038 H H H CH₃ 4-n-hex A038 H H H H 4-n-hex A038 H CH₃ H H 4-n-hex A038 H CH₂Ph H H 4-n-hex A038 H C(O)Ph H H 4-n-hex A038 H C(O)OEt H H 4-n-hex A038 H H H CH₃ 4-n-hex A038 H H CH₃ CH₃ 4-OCH₃ A038 H H H H 4-OCH₃ A038 H H H CH₃ 4-Ph A038 H H H H 4-Ph A038 H H H CH₃ H A038 2-OCH₃ H H H H A038 4-OCH₃ H H H H A038 4-F H H H H A039 H H H H H A039 3-CH₃ H H H H A039 7-OCH₃ H H H H A040 H H H H H A041 H H H H 4-Cl A041 H H H H 4-Cl A041 H H H CH₃ 4-CH₃ A041 H H H H 4-CH₃ A041 H CH₃ H H 4-CH₃ A041 H CH₂Ph H H 4-CH₃ A041 H C(O)Ph H H 4-CH₃ A041 H C(O)OEt H H 4-CH₃ A041 H H H CH₃ 4-CH₃ A041 H H CH₃ CH₃ 4-t-Bu A041 H H H H 4-t-Bu A041 H H H CH₃ 4-n-hex A041 H H H H 4-n-hex A041 H H H CH₃ 4-OCH₃ A041 H H H H 4-OCH₃ A041 H H H CH₃ 4-Ph A041 H H H H 4-Ph A041 H H H CH₃ H A041 6-NO₂ H H H H A041 6-Br H H H H A042 H H H H 4-Cl A042 H H H H 4-Cl A042 H H H CH₃ 4-CH₃ A042 H H H H 4-CH₃ A042 H CH₃ H H 4-CH₃ A042 H CH₂Ph H H 4-CH₃ A042 H C(O)Ph H H 4-CH₃ A042 H C(O)OEt H H 4-CH₃ A042 H H H CH₃ 4-CH₃ A042 H H CH₃ CH₃ 4-t-Bu A042 H H H H 4-t-Bu A042 H H H CH₃ 4-n-hex A042 H H H H 4-n-hex A042 H H H CH₃ 4-OCH₃ A042 H H H H 4-OCH₃ A042 H H H CH₃ 4-Ph A042 H H H H 4-Ph A042 H H H CH₃ H A042 5-Br H H H H A043 H H H H 4-Cl A043 H H H H 4-Cl A043 H H H CH₃ 4-CH₃ A043 H H H H 4-CH₃ A043 H CH₃ H H 4-CH₃ A043 H CH₂Ph H H 4-CH₃ A043 H C(O)Ph H H 4-CH₃ A043 H C(O)OEt H H 4-CH₃ A043 H H H CH₃ 4-CH₃ A043 H H CH₃ CH₃ 4-t-Bu A043 H H H H 4-t-Bu A043 H H H CH₃ 4-n-hex A043 H H H H 4-n-hex A043 H H H CH₃ 4-OCH₃ A043 H H H H 4-OCH₃ A043 H H H CH₃ 4-Ph A043 H H H H 4-Ph A043 H H H CH₃ H A044 H H H H 4-Cl A044 H H H H 4-Cl A044 H H H CH₃ 4-CH₃ A044 H H H H 4-CH₃ A044 H CH₃ H H 4-CH₃ A044 H CH₂Ph H H 4-CH₃ A044 H C(O)Ph H H 4-CH₃ A044 H C(O)OEt H H 4-CH₃ A044 H H H CH₃ 4-CH₃ A044 H H CH₃ CH₃ 4-t-Bu A044 H H H H 4-t-Bu A044 H H H CH₃ 4-n-hex A044 H H H H 4-n-hex A044 H H H CH₃ 4-OCH₃ A044 H H H H 4-OCH₃ A044 H H H CH₃ 4-Ph A044 H H H H 4-Ph A044 H H H CH₃ H A051 — H H H H A052 — H H H H A053 — H H H H A054 — H H H H A055 — H H H H A056 — H H H H A057 — H H H H A058 — H H H H A059 — H H H H A060 — H H H H A061 — H H H H A062 — H H H H A063 — H H H H A064 — H H H H A065 — H H H H A066 — H H H H A067 — H H H H A068 — H H H H A101 — H H H H A102 — H H H H A103 — H H H H A104 — H H H H A105 — H H H H A106 — H H H H A107 — H H H

TABLE 5

(Z) m (Z) m R² on ring of R² R⁸ on ring of R⁸ R³ R⁶ R⁷ H — c-Pr — H H H CH₃ — c-Pr — H H H H — c-Bu — H H H CH₃ — c-Bu — H H H H — c-Pen — H H H CH₃ — c-Pen — H H H H — c-Hex — H H H CH₃ — c-Hex — H H H CH₃ — c-Hex — CH₃ H H CH₃ — c-Hex — CH₂Ph H H CH₃ — c-Hex — C(O)Ph H H CH₃ — c-Hex — C(O)OEt H H CH₃ — c-Hex — H H CH₃ CH₃ — c-Hex — H CH₃ CH₃ C(O)CH₃ — c-Pr — H H H C(O)CH₃ — c-Hex — H H H C(O)CH₃ — c-Hex — CH₃ H H C(O)CH₃ — c-Hex — CH₂Ph H H C(O)CH₃ — c-Hex — C(O)Ph H H C(O)CH₃ — c-Hex — C(O)OEt H H C(O)CH₃ — c-Hex — H H CH₃ C(O)CH₃ — c-Hex — H CH₃ CH₃ C(O)Ph — c-Pr — H H H C(O)Ph — c-Hex — H H H C(O)Ph — c-Hex — CH₃ H H C(O)Ph — c-Hex — CH₂Ph H H C(O)Ph — c-Hex — C(O)Ph H H C(O)Ph — c-Hex — C(O)OEt H H C(O)Ph — c-Hex — H H CH₃ C(O)Ph — c-Hex — H CH₃ CH₃ A005 H A005 H H H H A005 H A006 H H H H A005 H A014 H H H H A005 H A016 2,4-(CH₃)₂ H H H A005 H A037 H H H H A005 H A038 H H H H A005 H A041 H H H H A005 H A042 H H H H A005 H A043 H H H H A005 H A044 H H H H A006 H A005 H H H H A006 H A006 H H H H A006 H A006 H CH₃ H H A006 H A006 H CH₂Ph H H A006 H A006 H C(O)Ph H H A006 H A006 H H H CH₃ A006 H A006 H H CH₃ CH₃ A006 H A014 H H H H A006 H A016 2,4-(CH₃)₂ CH H H A006 H A037 H H H H A006 H A037 H CH₃ H H A006 H A037 H CH₂Ph H H A006 H A037 H C(O)Ph H H A006 H A037 H H H CH₃ A006 H A037 H H CH₃ CH₃ A006 H A038 H H H H A006 H A038 H CH₃ H H A006 H A038 H CH₂Ph H H A006 H A038 H C(O)Ph H H A006 H A038 H H H CH₃ A006 H A038 H H CH₃ CH₃ A006 H A041 H H H H A006 H A041 H CH₃ H H A006 H A041 H CH₂Ph H H A006 H A041 H C(O)Ph H H A006 H A041 H H H CH₃ A006 H A041 H H CH₃ CH₃ A006 H A042 H H H H A006 H A042 H CH₃ H H A006 H A042 H CH₂Ph H H A006 H A042 H C(O)Ph H H A006 H A042 H H H CH₃ A006 H A042 H H CH₃ CH₃ A006 H A043 H H H H A006 H A044 H H H H A014 H A005 H H H H A014 H A006 H H H H A014 H A014 H H H H A014 H A016 2,4-(CH₃)₂ H H H A014 H A037 H H H H A014 H A038 H H H H A014 H A041 H H H H A014 H A042 H H H H A014 H A043 H H H H A014 H A044 H H H H A016 2,4-(CH₃)₂ A005 H H H H A016 2,4-(CH₃)₂ A006 H H H H A016 2,4-(CH₃)₂ A014 H H H H A016 2,4-(CH₃)₂ A016 2,4-(CH₃)₂ H H H A016 2,4-(CH₃)₂ A037 H H H H A016 2,4-(CH₃)₂ A038 H H H H A016 2,4-(CH₃)₂ A041 H H H H A016 2,4-(CH₃)₂ A042 H H H H A016 2,4-(CH₃)₂ A043 H H H H A016 2,4-(CH₃)₂ A044 H H H H A036 H A005 H H H H A036 H A006 H H H H A036 H A014 H H H H A036 H A016 2,4-(CH₃)₂ H H H A036 H A037 H H H H A036 H A038 H H H H A036 H A041 H H H H A036 H A042 H H H H A036 H A043 H H H H A036 H A044 H H H H A037 H A005 H H H H A037 H A006 H H H H A037 H A006 H CH₃ H H A037 H A006 H CH₂Ph H H A037 H A006 H C(O)Ph H H A037 H A006 H H H CH₃ A037 H A006 H H CH₃ CH₃ A037 H A014 H H H H A037 H A016 2,4-(CH₃)₂ H H H A037 H A037 H H H H A037 H A037 H CH₃ H H A037 H A037 H CH₂Ph H H A037 H A037 H C(O)Ph H H A037 H A037 H H H CH₃ A037 H A037 H H CH₃ CH₃ A037 H A038 H H H H A037 H A038 H CH₃ H H A037 H A038 H CH₂Ph H H A037 H A038 H C(O)Ph H H A037 H A038 H H H CH₃ A037 H A038 H H CH₃ CH₃ A037 H A041 H H H H A037 H A041 H CH₃ H H A037 H A041 H CH₂Ph H H A037 H A041 H C(O)Ph H H A037 H A041 H H H CH₃ A037 H A041 H H CH₃ CH₃ A037 H A042 H H H H A037 H A042 H CH₃ H H A037 H A042 H CH₂Ph H H A037 H A042 H C(O)Ph H H A037 H A042 H H H CH₃ A037 H A042 H H CH₃ CH₃ A037 H A043 H H H H A037 H A044 H H H H A038 H A005 H H H H A038 H A006 H H H H A038 H A006 H CH₃ H H A038 H A006 H CH₂Ph H H A038 H A006 H C(O)Ph H H A038 H A006 H H H CH₃ A038 H A006 H H CH₃ CH₃ A038 H A014 H H H H A038 H A016 2,4-(CH₃)₂ H H H A038 H A037 H H H H A038 H A037 H CH₃ H H A038 H A037 H CH₂Ph H H A038 H A037 H C(O)Ph H H A038 H A037 H H H CH₃ A038 H A037 H H CH₃ CH₃ A038 H A038 H H H H A038 H A038 H CH₃ H H A038 H A038 H CH₂Ph H H A038 H A038 H C(O)Ph H H A038 H A038 H H H CH₃ A038 H A038 H H CH₃ CH₃ A038 H A041 H H H H A038 H A041 H CH₃ H H A038 H A041 H CH₂Ph H H A038 H A041 H C(O)Ph H H A038 H A041 H H H CH₃ A038 H A041 H H CH₃ CH₃ A038 H A042 H H H H A038 H A042 H CH₃ H H A038 H A042 H CH₂Ph H H A038 H A042 H C(O)Ph H H A038 H A042 H H H CH₃ A038 H A042 H H CH₃ CH₃ A038 H A043 H H H H A038 H A044 H H H H A041 H A005 H H H H A041 H A006 H H H H A041 H A006 H CH₃ H H A041 H A006 H CH₂Ph H H A041 H A006 H C(O)Ph H H A041 H A006 H H H CH₃ A041 H A006 H H CH₃ CH₃ A041 H A014 H H H H A041 H A016 2,4-(CH₃)₂ H H H A041 H A037 H H H H A041 H A037 H CH₃ H H A041 H A037 H CH₂Ph H H A041 H A037 H C(O)Ph H H A041 H A037 H H H CH₃ A041 H A037 H H CH₃ CH₃ A041 H A038 H H H H A041 H A038 H CH₃ H H A041 H A038 H CH₂Ph H H A041 H A038 H C(O)Ph H H A041 H A038 H H H CH₃ A041 H A038 H H CH₃ CH₃ A041 H A041 H H H H A041 H A041 H CH₃ H H A041 H A041 H CH₂Ph H H A041 H A041 H C(O)Ph H H A041 H A041 H H H CH₃ A041 H A041 H H CH₃ CH₃ A041 H A042 H H H H A041 H A042 H CH₃ H H A041 H A042 H CH₂Ph H H A041 H A042 H C(O)Ph H H A041 H A042 H H H CH₃ A041 H A042 H H CH₃ CH₃ A041 H A043 H H H H A041 H A044 H H H H A042 H A005 H H H H A042 H A006 H H H H A042 H A006 H CH₃ H H A042 H A006 H CH₂Ph H H A042 H A006 H C(O)Ph H H A042 H A006 H H H CH₃ A042 H A006 H H CH₃ CH₃ A042 H A014 H H H H A042 H A016 2,4-(CH₃)₂ H H H A042 H A037 H H H H A042 H A037 H CH₃ H H A042 H A037 H CH₂Ph H H A042 H A037 H C(O)Ph H H A042 H A037 H H H CH₃ A042 H A037 H H CH₃ CH₃ A042 H A038 H H H H A042 H A038 H CH₃ H H A042 H A038 H CH₂Ph H H A042 H A038 H C(O)Ph H H A042 H A038 H H H CH₃ A042 H A038 H H CH₃ CH₃ A042 H A041 H H H H A042 H A041 H CH₃ H H A042 H A041 H CH₂Ph H H A042 H A041 H C(O)Ph H H A042 H A041 H H H CH₃ A042 H A041 H H CH₃ CH₃ A042 H A042 H H H H A042 H A042 H CH₃ H H A042 H A042 H CH₂Ph H H A042 H A042 H C(O)Ph H H A042 H A042 H H H CH₃ A042 H A042 H H CH₃ CH₃ A042 H A043 H H H H A042 H A044 H H H H The expression — indicates unsubstituted.

TABLE 6 The locants for the substituents R¹¹, R²¹ and R⁸¹ in the Table corre- spond to the positions indicated in the following structural formulae.

R¹¹ R²¹ R⁸¹ R³ R⁶ R⁷ H H H H H H H 4-CH₃ H H H H H 4-t-Bu H H H H H 4-t-Bu 4-CH₃ H H H H 4-t-Bu H CH₃ H H H 4-t-Bu 4-CH₃ CH₃ H H H 4-n-Hex H H H H H 4-n-Hex 4-Cl H H H H 4-n-Hex 4-Br H H H H 4-n-Hex 4-CH₃ H H H H 4-n-Hex H CH₃ H H H 4-n-Hex 4-CH₃ CH₃ H H H 4-n-Hex H CH₂Ph H H H 4-n-Hex H C(O)OEt H H H 4-n-Hex H C(O)Ph H H H 4-n-Hex H H H CH₃ H 4-n-Hex H H CH₃ CH₃ H 4-Ph H H H H H 4-Ph 4-CH₃ H H H H 4-Ph H CH₃ H H H 4-Ph 4-CH₃ CH₃ H H 4-F H H H H H 2-Cl H H H H H 3-Cl H H H H H 4-Cl H H H H H 4-Cl 4-t-Bu H H H H 4-Cl 4-t-Bu 4-CH₃ H H H 4-Cl 4-n-Hex H H H H 4-Cl 4-n-Hex 4-Cl H H H 4-Cl 4-n-Hex 4-Br H H H 4-Cl 4-n-Hex 4-CH₃ H H H 4-Cl 4-Ph H H H H 4-Cl 4-Ph 4-CH₃ H H H 4-Br H H H H H 3,4-Cl₂ H H H H H 4-NO₃ H H H H H 4-CN H H H H H 2-CH₃ H H H H H 3-CH₃ H H H H H 4-CH₃ H H H H H 4-CH₃ 4-t-Bu H H H H 4-CH₃ 4-t-Bu 4-CH₃ H H H 4-CH₃ 4-n-Hex H H H H 4-CH₃ 4-n-Hex 4-Cl H H H 4-CH₃ 4-n-Hex 4-Br H H H 4-CH₃ 4-n-Hex 4-CH₃ H H H 4-CH₃ 4-Ph H H H H 4-CH₃ 4-Ph 4-CH₃ H H H 3,4-(CH₃)₂ H H H H H 4-OCH₃ H H H H H 4-OCH₃ 4-t-Bu H H H H 4-OCH₃ 4-n-Hex H H H H 4-OCH₃ 4-n-Hex 4-Cl H H H 4-OCH₃ 4-n-Hex 4-Br H H H 4-OCH₃ 4-n-Hex 4-CH₃ H H H 4-OCH₃ 4-Ph H H H H 3,4-(OCH₃) H H H H H 4-Ph H H H H H

TABLE 7 The locants for the substituent R⁸¹ in the Table correspond to the positions indicated in the following structural formulae.

R¹ R² (Z)m R⁸¹ R³ R⁶ R⁷ H H — H H H H Et H — H H H H n-Pr H — H H H H n-Bu H — H H H H c-Bu H — H H H H n-Pen H — H H H H c-Pen H — H H H H CF₃ H — H H H H CF₃ H — 4-CH₃ H H H CF₃ H — 4-CH₃ CH₃ H H CF₃ A005 — H H H H CF₃ A006 — H H H H CF₃ A014 H H H H CF₃ A016 2,4-(CH₃)₂ H H H H CF₃ A036 H H H H H CF₃ A037 — H H H H CF₃ A038 — H H H H CF₃ A041 — H H H H CF₃ A042 — H H H H CN H — H H H H C(O)OEt H — H H H H Ph H — H H H H (4-CH₃)Ph H — H H H H (4-i-Pr)Ph H — H H H H (4-OCH₃)Ph H — H H H H (4-OCH₃)Ph H — 4-CH₃ H H H

TABLE 8 The locants for the substituents R²¹ and R⁸¹ in the Table correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R¹ (Z)m R²¹ R⁸¹ R³ R⁶ R⁷ H — H H H H H Et — H H H H H n-Pr — H H H H H n-Bu — H H H H H CF₃ — H H H H H CF₃ — 4-CH₃ H H H H CF₃ — 4-CH₃ 4-CH₃ H H H CF₃ — 4-CH₃ 4-CH₃ CH₃ H H CF₃ — 4-CH₃ 4-CH₃ H H CH₃ CF₃ — 4-t-Bu H H H H CF₃ — 4-n-Hex 4-CH₃ H H H CF₃ — 4-n-Hex 4-CH₃ CH₃ H H CF₃ — 4-n-Hex 4-CH₃ H H CH₃ CF₃ — 4-n-Hex 4-CH₃ H CH₃ CH₃ CF₃ — 4-Ph H H H H CO₂Et — H H H H H A001 H H H H H H A002 H H H H H H A003 H H H H H H A005 H H H H H H A005 2,5-(CH₃)₂ H H H H H A005 2,5-Cl₂ H H H H H A005 2-Br H H H H H A006 H H H H H H A006 3-CH₃ H H H H H A006 5-CH₃ H H H H H A006 3-Cl H H H H H A006 5-Et H H H H H A006 5-Cl H H H H H A006 5-Br H H H H H A006 3-Br H H H H H A006 4-Br H H H H H A006 5-NO₂ H H H H H A007 H H H H H H A007 5-CH₃ H H H H H A007 3-CH₃ H H H H H A007 5-Br H H H H H A007 5-NO₂ H H H H H A007 5-Ph H H H H H A008 5-CH₃ H H H H H A009 5-CH₃ H H H H H A010 3,5-(CH₃)₂ H H H H H A010 3,5-Cl₂ H H H H H A011 3,5-(CH₃)₂ H H H H H A011 3,5-Cl₂ H H H H H A012 3-CH₃ H H H H H A012 3-CH₃ H H H H H A012 3-Cl H H H H H A013 3-CH₃ H H H H H A013 3-CH₃ H H H H H A013 3-Cl H H H H H A014 H H H H H H A015 H H H H H H A016 2,4-(CH₃)₂ H H H H H A017 2,4-(CH₃)₂ H H H H H A034 H H H H H H A034 3,6-Cl₂ H H H H H A035 H H H H H H A036 H H H H H H A037 H H H H H H A037 6-OCH₃ H H H H H A037 6-Br H H H H H A038 H H H H H H A038 2-OCH₃ H H H H H A038 4-OCH₃ H H H H H A038 4-F H H H H H

TABLE 9 The locants for the substituent R²¹ and R⁸¹ in the Table correspond to the positions indicated in the following structural formulae.

R²¹ R⁸¹ R³ H H H H 4-F H H 2-Cl H H 3-Cl H H 4-Cl H H 4-Cl CH₃ H 4-Cl CH₂Ph H 4-Cl C(O)Ph H 4-Cl C(O)OEt H 4-Br H H 4-I H H 2,4-Cl₂ H H 3,4-Cl₂ H H 4-NO₂ H H 4-CN H H 2-CH₃ H H 3-CH₃ H H 4-CH₃ H H 4-CH₃ CH₃ H 4-CH₃ CH₂Ph H 4-CH₃ C(O)Ph H 4-CH₃ C(O)OEt H 4-Et H H 4-n-Pr H H 4-c-Pr H H 4-i-Pr H H 4-n-Bu H H 4-c-Bu H H 4-i-Bu H H 4-t-Bu H H 4-t-Bu CH₃ H 4-t-Bu CH₂Ph H 4-t-Bu C(O)Ph H 4-t-Bu C(O)OEt H 4-n-Pen H H 4-c-Pen H H 4-n-Hex H H 4-n-Hex CH₃ H 4-n-Hex CH₂Ph H 4-n-Hex C(O)Ph H 4-n-Hex C(O)OEt H 4-c-Hex H H 4-n-C₇H₁₅ H H 4-n-C₈H₁₇ H H 4-n-C₉H₁₉ H H 4-n-C₁₀H₂₁ H H 2,4-(CH₃) H H 3,4-(CH₃)₂ H H 4-CF₃ H H 4-OH H H 2-OCH₃ H H 3-OCH₃ H H 4-OCH₃ H H 4-O-n-Hex H H 4-O-c-Hex H H 2,4-(OCH₃)₂ H H 3,4-(OCH₃)₂ H H 4-OCH₂OCH₃ H H 4-OC₂H₄OEt H H 4-OCF₃ H H 4-OPh H H 4-OCH₂Ph H H 4-C(CH₃)═NCH₃ H H 4-C(CH₃)═NPh H H 4-C(Ph)═NCH₃ H H 4-C(Ph)═NPh H H 4-C(CH₃)═NOCH₃ H H 4-C(CH₃)═NOPh H H 4-C(Ph)═NOCH₃ H H 4-C(Ph)═NOPh H H 4-C(O)CH₃ H H 4-C(O)CF₃ H H 4-C(O)Ph H H 4-C(O)OCH₃ H H 2-C(O)OEt H H 3-C(O)OEt H H 4-C(O)OEt H H 4-C(O)OPh H H 4-C(O)OCH₂Ph H H 4-C(O)OCH(CH₃)Ph H H 4-C(O)OC₂H₄Ph H H 4-SCH₃ H H 4-S(O)CH₃ H H 4-S(O)₂CH₃ H H 4-SPh H H 4-S(O)Ph H H 4-S(O)₂Ph H H 4-OS(O)₂CH₃ H H 4-OS(O)₂Ph H H 4-N(CH₃)₂ H H 4-N(CH₂Ph)₂ H H 4-N(CH₃) (CH₂Ph) H H 4-NHCH₃ H H 4-NH(CH₂Ph) H H 4-C(O)N(CH₃)₂ H H 4-C(O)N(CH₂Ph)₂ H H 4-C(O)N(CH₃) (CH₃Ph) H H 4-C(O)NHCH₃ H H 4-C(O)NH(CH₂Ph) H H 4-C(O)NH(CH (CH₃)Ph) H H 4-C(O)NH(C₂H₄Ph) H H 4-C(S)NH₂ H H 4-S(O)₂N(CH₃)₂ H H 4-S(O)₂N(CH₂Ph)₂ H H 4-S(O)₂N(CH₃) (CH₂Ph) H H 4-S(O)₂NHCH₃ H H 4-S(O)₂NHPh H H 4-S(O)₂NH(CH₂Ph) H H 4-S(O)₂NH{CH(CH₃)Ph} H H 4-S(O)₂NH(C₂H₄Ph) H H 4-Ph H H 4-Ph CH₃ H 4-Ph CH₂Ph H 4-Ph C(O)Ph H 4-Ph C(O)OEt 4-F H H 4-F 4-Cl H 4-F 4-Br H 4-F 4-CH₃ H 4-F 4-t-Bu H 4-F 4-n-Hex H 4-F 4-Ph H 2-Cl H H 2-Cl 4-Cl H 2-Cl 4-Br H 2-Cl 4-CH₃ H 2-Cl 4-t-Bu H 2-Cl 4-n-Hex H 2-Cl 4-Ph H 3-Cl H H 3-Cl 4-Cl H 3-Cl 4-Br H 3-Cl 4-CH₃ H 3-Cl 4-t-Bu H 3-Cl 4-n-Hex H 3-Cl 4-Ph H 4-Cl H H 4-Cl 4-Cl H 4-Cl 4-Br H 4-Cl 4-CH₃ H 4-Cl 4-t-Bu H 4-Cl 4-t-Bu CH₃ 4-Cl 4-n-Hex H 4-Cl 4-n-Hex CH₃ 4-Cl 4-Ph H 4-Cl 4-Ph CH₃ 4-Br H H 4-Br 4-Cl H 4-Br 4-Br H 4-Br 4-CH₃ H 4-Br 4-t-Bu H 4-Br 4-n-Hex H 4-Br 4-Ph H 3,4-Cl₂ H H 3,4-Cl₂ 4-Cl H 3,4-Cl₂ 4-Br H 3,4-Cl₂ 4-CH₃ H 3,4-Cl₂ 4-t-Bu H 3,4-Cl₂ 4-n-Hex H 3,4-Cl₂ 4-Ph H 4-NO₂ H H 4-NO₂ 4-Cl H 4-NO₂ 4-Br H 4-NO₂ 4-CH₃ H 4-NO₂ 4-t-Bu H 4-NO₂ 4-n-Hex H 4-NO₂ 4-Ph H 4-CN H H 4-CN 4-Cl H 4-CN 4-Br H 4-CN 4-CH₃ H 4-CN 4-t-Bu H 4-CN 4-n-Hex H 4-CN 4-Ph H 2-CH₃ H H 2-CH₃ 4-Cl H 2-CH₃ 4-Br H 2-CH₃ 4-CH₃ H 2-CH₃ 4-t-Bu H 2-CH₃ 4-n-Hex H 2-CH₃ 4-Ph H 3-CH₃ H H 3-CH₃ 4-Cl H 3-CH₃ 4-Br H 3-CH₃ 4-CH₃ H 3-CH₃ 4-t-Bu H 3-CH₃ 4-n-Hex H 3-CH₃ 4-Ph H 4-CH₃ H H 4-CH₃ 4-Cl H 4-CH₃ 4-Br H 4-CH₃ 4-CH₃ H 4-CH₃ 4-t-Bu H 4-CH₃ 4-t-Bu CH₃ 4-CH₃ 4-n-Hex H 4-CH₃ 4-n-Hex CH₃ 4-CH₃ 4-Ph H 4-CH₃ 4-Ph CH₃ 4-c-Pr H H 4-c-Pr 4-Cl H 4-c-Pr 4-Br H 4-c-Pr 4-CH₃ H 4-c-Pr 4-t-Bu H 4-c-Pr 4-n-Hex H 4-c-Pr 4-Ph H 4-i-Pr H H 4-i-Pr 4-Cl H 4-i-Pr 4-Br H 4-i-Pr 4-CH₃ H 4-i-Pr 4-t-Bu H 4-i-Pr 4-n-Hex H 4-i-Pr 4-Ph H 4-t-Bu H H 4-t-Bu 4-Cl H 4-t-Bu 4-Br H 4-t-Bu 4-CH₃ H 4-t-Bu 4-t-Bu H 4-t-Bu 4-t-Bu CH₃ 4-t-Bu 4-n-Hex H 4-t-Bu 4-n-Hex CH₃ 4-t-Bu 4-Ph H 4-t-Bu 4-Ph CH₃ 4-n-Hex H H 4-n-Hex H CH₃ 4-n-Hex H CH₂Ph 4-n-Hex H C(O)Ph 4-n-Hex H C(O)OEt 4-n-Hex 4-F H 4-n-Hex 2-Cl H 4-n-Hex 3-Cl H 4-n-Hex 4-Cl H 4-n-Hex 4-Cl CH₃ 4-n-Hex 4-Cl CH₂Ph 4-n-Hex 4-Cl C(O)Ph 4-n-Hex 4-Cl C(O)OEt 4-n-Hex 4-Br H 4-n-Hex 4-I H 4-n-Hex 2,4-Cl₂ H 4-n-Hex 3,4-Cl₂ H 4-n-Hex 4-NO₂ H 4-n-Hex 4-CN H 4-n-Hex 2-CH₃ H 4-n-Hex 3-CH₃ H 4-n-Hex 4-CH₃ H 4-n-Hex 4-CH₃ CH₃ 4-n-Hex 4-CH₃ CH₂Ph 4-n-Hex 4-CH₃ C(O)Ph 4-n-Hex 4-CH₃ C(O)OEt 4-n-Hex 4-Et H 4-n-Hex 4-n-Pr H 4-n-Hex 4-c-Pr H 4-n-Hex 4-i-Pr H 4-n-Hex 4-n-Bu H 4-n-Hex 4-c-Bu H 4-n-Hex 4-i-Bu H 4-n-Hex 4-t-Bu H 4-n-Hex 4-t-Bu CH₃ 4-n-Hex 4-t-Bu CH₂Ph 4-n-Hex 4-t-Bu C(O)Ph 4-n-Hex 4-t-Bu C(O)OEt 4-n-Hex 4-n-Pen H 4-n-Hex 4-c-Pen H 4-n-Hex 4-n-Hex H 4-n-Hex 4-n-Hex CH₃ 4-n-Hex 4-n-Hex CH₂Ph 4-n-Hex 4-n-Hex C(O)Ph 4-n-Hex 4-n-Hex C(O)OEt 4-n-Hex 4-c-Hex H 4-n-Hex 4-n-C₇H₁₅ H 4-n-Hex 4-n-C₈H₁₇ H 4-n-Hex 4-n-C₉H₁₉ H 4-n-Hex 4-n-C₁₀H₂₁ H 4-n-Hex 2,4-(CH₃) H 4-n-Hex 3,4-(CH₃)₂ H 4-n-Hex 4-CF₃ H 4-n-Hex 4-OH H 4-n-Hex 2-OCH₃ H 4-n-Hex 3-OCH₃ H 4-n-Hex 4-OCH₃ H 4-n-Hex 4-O-n-Hex H 4-n-Hex 4-O-c-Hex H 4-n-Hex 2,4-(OCH₃)₂ H 4-n-Hex 3,4-(OCH₃)₂ H 4-n-Hex 4-OCH₂OCH₃ H 4-n-Hex 4-OC₂H₄OEt H 4-n-Hex 4-OCF₃ H 4-n-Hex 4-OPh H 4-n-Hex 4-OCH₂Ph H 4-n-Hex 4-C(CH₃)═NCH₃ H 4-n-Hex 4-C(CH₃)═NPh H 4-n-Hex 4-C(Ph)═NCH₃ H 4-n-Hex 4-C(Ph)═NPh H 4-n-Hex 4-C(CH₃)═NOCH₃ H 4-n-Hex 4-C(CH₃)═NOPh H 4-n-Hex 4-C(Ph)═NOCH₃ H 4-n-Hex 4-C(Ph)═NOPh H 4-n-Hex 4-C(O)CH₃ H 4-n-Hex 4-C(O)CF₃ H 4-n-Hex 4-C(O)Ph H 4-n-Hex 4-C(O)OCH₃ H 4-n-Hex 2-C(O)OEt H 4-n-Hex 3-C(O)OEt H 4-n-Hex 4-C(O)OEt H 4-n-Hex 4-C(O)OPh H 4-n-Hex 4-C(O)OCH₂Ph H 4-n-Hex 4-C(O)OCH(CH₃)Ph H 4-n-Hex 4-C(O)OC₂H₄Ph H 4-n-Hex 4-SCH₃ H 4-n-Hex 4-S(O)CH₃ H 4-n-Hex 4-5(O)₂CH₃ H 4-n-Hex 4-SPh H 4-n-Hex 4-S(O)Ph H 4-n-Hex 4-S(O)₂Ph H 4-n-Hex 4-OS(O)₂CH₃ H 4-n-Hex 4-OS(O)₂Ph H 4-n-Hex 4-N(CH₃)₂ H 4-n-Hex 4-N(CH₂Ph)₂ H 4-n-Hex 4-N(CH₃) (CH₂Ph) H 4-n-Hex 4-NHCH₃ H 4-n-Hex 4-NH(CH₂Ph) H 4-n-Hex 4-C(O)N(CH₃)₂ H 4-n-Hex 4-C(O)N(CH₂Ph)₂ H 4-n-Hex 4-C(O)N(CH₃) (CH₂Ph) H 4-n-Hex 4-C(O)NHCH₃ H 4-n-Hex 4-C(O)NH(CH₂Ph) H 4-n-Hex 4-C(O)NH{CH(CH₃)Ph} H 4-n-Hex 4-C(O)NH(C₂H₄Ph) H 4-n-Hex 4-C(S)NH₂ H 4-n-Hex 4-S(O)₂N(CH₃)₂ H 4-n-Hex 4-S(O)₂N(CH₂Ph)₂ H 4-n-Hex 4-S(O)₂N(CH₃) (CH₂Ph) H 4-n-Hex 4-S(O)₂NHCH₃ H 4-n-Hex 4-S(O)₂NHPh H 4-n-Hex 4-S(O)₂NH(CH₂Ph) H 4-n-Hex 4-S(O)₂NH{CH(CH₃)Ph} H 4-n-Hex 4-S(O)₂NH(C₂H₄Ph) H 4-n-Hex 4-Ph H 4-n-Hex 4-Ph CH₃ 4-n-Hex 4-Ph CH₂Ph 4-n-Hex 4-Ph C(O)Ph 4-n-Hex 4-Ph C(O)OEt 4-c-Hex H H 4-c-Hex 4-Cl H 4-c-Hex 4-Br H 4-c-Hex 4-CH₃ H 4-c-Hex 4-t-Bu H 4-c-Hex 4-t-Bu CH₃ 4-c-Hex 4-n-Hex H 4-c-Hex 4-n-Hex CH₃ 4-c-Hex 4-Ph H 4-c-Hex 4-Ph CH₃ 3,4-(CH₃)₂ H H 3,4-(CH₃)₂ 4-Cl H 3,4-(CH₃)₂ 4-Br H 3,4-(CH₃)₂ 4-CH₃ H 3,4-(CH₃)₂ 4-t-Bu H 3,4-(CH₃)₂ 4-n-Hex H 3,4-(CH₃)₂ 4-Ph H 2,4-(t-Bu)₂ H H 2,4-(t-Bu)₂ 4-Cl H 2,4-(t-Bu)₂ 4-Br H 2,4-(t-Bu)₂ 4-CH₃ H 2,4-(t-Bu)₂ 4-t-Bu H 2,4-(t-Bu)₂ 4-n-Hex H 2,4-(t-Bu)₂ 4-Ph H 4-CF₃ H H 4-CF₃ 4-Cl H 4-CF₃ 4-Br H 4-CF₃ 4-CH₃ H 4-CF₃ 4-t-Bu H 4-CF₃ 4-n-Hex H 4-CF₃ 4-Ph H 4-OH H H 4-OH 4-Cl H 4-OH 4-Br H 4-OH 4-CH₃ H 4-OH 4-t-Bu H 4-OH 4-n-Hex H 4-OH 4-Ph H 4-OCH₃ H H 4-OCH₃ 4-Cl H 4-OCH₃ 4-Br H 4-OCH₃ 4-CH₃ H 4-OCH₃ 4-t-Bu H 4-OCH₃ 4-n-Hex H 4-OCH₃ 4-Ph H 4-O-i-Pr H H 4-O-i-Pr 4-Cl H 4-O-i-Pr 4-Br H 4-O-i-Pr 4-CH₃ H 4-O-i-Pr 4-t-Bu H 4-O-i-Pr 4-n-Hex H 4-O-i-Pr 4-Ph H 4-O-n-Hex H H 4-O-n-Hex 4-Cl H 4-O-n-Hex 4-Br H 4-O-n-Hex 4-CH₃ H 4-O-n-Hex 4-t-Bu H 4-O-n-Hex 4-n-Hex H 4-O-n-Hex 4-Ph H 3,4-(OCH₃)₂ H H 3,4-(OCH₃)₂ 4-Cl H 3,4-(OCH₃)₂ 4-Br H 3,4-(OCH₃)₂ 4-CH₃ H 3,4-(OCH₃)₂ 4-t-Bu H 3,4-(OCH₃)₂ 4-n-Hex H 3,4-(OCH₃)₂ 4-Ph H 4-OC₂H₄OEt H H 4-OC₂H₄OEt 4-Cl H 4-OC₂H₄OEt 4-Br H 4-OC₂H₄OEt 4-CH₃ H 4-OC₂H₄OEt 4-t-Bu H 4-OC₂H₄OEt 4-n-Hex H 4-OC₂H₄OEt 4-Ph H 4-OPh H H 4-OPh 4-Cl H 4-OPh 4-Br H 4-OPh 4-CH₃ H 4-OPh 4-t-Bu H 4-OPh 4-n-Hex H 4-OPh 4-Ph H 4-OCH₂Ph H H 4-OCH₂Ph 4-Cl H 4-OCH₂Ph 4-Br H 4-OCH₂Ph 4-CH₃ H 4-OCH₂Ph 4-t-Bu H 4-OCH₂Ph 4-n-Hex H 4-OCH₂Ph 4-Ph H 4-Ph H H 4-Ph 4-Cl H 4-Ph 4-Br H 4-Ph 4-CH₃ H 4-Ph 4-t-Bu H 4-Ph 4-t-Bu CH₃ 4-Ph 4-n-Hex H 4-Ph 4-n-Hex CH₃ 4-Ph 4-Ph H 4-Ph 4-Ph CH₃

TABLE 10 The locants for the substituent R⁸¹ in the Table correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R² (Z)m R⁸¹ R³ H — H H H — 4-CH₃ H F — H H CH₃ — H H Et — H H n-Pr — H H c-Pr — H H i-Pr — H H n-Bu — H H c-Bu — H H i-Bu — H H t-Bu — H H n-Pen — H H c-Pen — H H n-Hex — H H c-Hex — H H n-C₇H₁₅ — H H n-C₈H₁₇ — H H n-C₉H₁₉ — H H n-C₁₀H₂ — H H CF₃ — H H C(Ph)═NCH₃ — H H C(CH₃)═NPh — H H C(Ph)═NOCH₃ — H H C(O)CH₃ — H H C(O)Et — H H C(O)CF₃ — H H C(O)Ph — H H C(O)Ph — 4-Cl H C(O)Ph — 4-CH₃ H C(O)Ph — 4-CH₃ CH₃ C(O)Ph — 4-CH₃ CH₂Ph C(O)Ph — 4-CH₃ C(O)Ph C(O)Ph — 4-CH₃ C(O)OEt C(O)Ph — 4-t-Bu H C(O)Ph — 4-n-hex H C(O)Ph — 4-OCH₃ H C(O)Ph — 4-Ph H C(O)CH₂Ph — H H C(O)CH(CH₃)Ph — H H C(O)C₂H₄Ph — H H C(O)OCH₃ — H H C(O)OEt — H H C(O)OEt — 4-Cl H C(O)OEt — 4-CH₃ H C(O)OEt — 4-CH₃ CH₃ C(O)OEt — 4-CH₃ CH₂Ph C(O)OEt — 4-CH₃ C(O)Ph C(O)OEt — 4-CH₃ C(O)OEt C(O)OEt — 4-t-Bu H C(O)OEt — 4-n-hex H C(O)OEt — 4-OCH₃ H C(O)OEt — 4-Ph H C(O)OPh — H H C(O)OCH₂Ph — H H C(O)OCH(CH3)Ph — H H C(O)OC₂H₄Ph — H H C(O)N(CH₃)₂ — H H C(O)NHCH₃ — H H C(O)NH(CH₂Ph) — H H CH₂Ph — H H CH₂(4-Cl-Ph) — H H A001 H H H A001 3-n-Bu H H A002 H H H A002 2-Cl H H A003 H H H A004 H H H A005 H H H A005 H 4-Cl H A005 H 4-CH₃ H A005 H 4-CH₃ CH₃ A005 H 4-CH₃ CH₂Ph A005 H 4-CH₃ C(O)Ph A005 H 4-CH₃ C(O)OEt A005 H 4-t-Bu H A005 H 4-n-hex H A005 H 4-OCH₃ H A005 H 4-Ph H A005 2,5-(CH₃)₂ H H A005 2,5-Cl₂ H H A005 2-Br H H A006 H H H A006 H 4-Cl H A006 H 4-CH₃ H A006 H 4-CH₃ CH₃ A006 H 4-CH₃ CH₂Ph A006 H 4-CH₃ C(O)Ph A006 H 4-CH₃ C(O)OEt A006 H 4-t-Bu H A006 H 4-n-hex H A006 H 4-OCH₃ H A006 H 4-Ph H A006 3-CH₃ H H A006 5-CH₃ H H A006 3-Cl H H A006 5-Et H H A006 5-Cl H H A006 5-Br H H A006 3-Br H H A006 4-Br H H A006 5-NO₂ H H A007 H H H A007 5-CH₃ H H A007 3-CH₃ H H A007 5-Br H H A007 5-NO₂ H H A007 5-Ph H H A008 5-CH₃ H H A009 5-CH₃ H H A010 3,5-(CH₃)₂ H H A010 3,5-Cl₂ H H A011 3,5-(CH₃)₂ H H A011 3,5-Cl₂ H H A012 3-CH₃ H H A012 3-CH₃ H H A012 3-Cl H H A013 3-CH₃ H H A013 3-CH₃ H H A013 3-Cl H H A014 H H H A014 H 4-Cl H A014 H 4-CH₃ H A014 H 4-CH₃ CH₃ A014 H 4-CH₃ CH₂Ph A014 H 4-CH₃ C(O)Ph A014 H 4-CH₃ C(O)OEt A014 H 4-t-Bu H A014 H 4-n-hex H A014 H 4-OCH₃ H A014 H 4-Ph H A015 H H H A016 2,4-(CH₃)₂ H H A016 2,4-(CH₃)₂ 4-Cl H A016 2,4-(CH₃)₂ 4-CH₃ H A016 2,4-(CH₃)₂ 4-CH₃ CH₃ A016 2,4-(CH₃)₂ 4-CH₃ CH₂Ph A016 2,4-(CH₃)₂ 4-CH₃ C(O)Ph A016 2,4-(CH₃)₂ 4-CH₃ C(O)OEt A016 2,4-(CH₃)₂ 4-t-Bu H A016 2,4-(CH₃)₂ 4-n-hex H A016 2,4-(CH₃)₂ 4-OCH₃ H A016 2,4-(CH₃)₂ 4-Ph H A017 2,4-(CH₃)₂ H H A018 H H H A018 3-CH₃ H H A019 3-Ph, 5-CH₃ H H A019 3,5-(CH₃)₂ H H A020 5-CH₃ H H A021 4-CH₃ H H A022 H H H A023 2,4-(CH₃)₂ H H A024 2-(4-pyridil) H H A025 H H H A026 H H H A026 4-CH₃ H H A027 H H H A027 4-CH₃ H H A028 H H H A029 H H H A030 H H H A031 H H H A032 H H H A033 H H H A034 H H H A034 3,6-Cl₂ H H A035 H H H A036 H H H A036 H 4-Cl H A036 H 4-CH₃ H A036 H 4-CH₃ CH₃ A036 H 4-CH₃ CH₂Ph A036 H 4-CH₃ C(O)Ph A036 H 4-CH₃ C(O)OEt A036 H 4-t-Bu H A036 H 4-n-hex H A036 H 4-OCH₃ H A036 H 4-Ph H A037 H H H A037 H 4-Cl H A037 H 4-CH₃ H A037 H 4-CH₃ CH₃ A037 H 4-CH₃ CH₂Ph A037 H 4-CH₃ C(O)Ph A037 H 4-CH₃ C(O)OEt A037 H 4-t-Bu H A037 H 4-n-hex H A037 H 4-OCH₃ H A037 H 4-Ph H A037 6-OCH₃ H H A037 6-Br H H A038 H H H A038 H 4-Cl H A038 H 4-CH₃ H A038 H 4-CH₃ CH₃ A038 H 4-CH₃ CH₂Ph A038 H 4-CH₃ C(O)Ph A038 H 4-CH₃ C(O)OEt A038 H 4-t-Bu H A038 H 4-n-hex H A038 H 4-OCH₃ H A038 H 4-Ph H A038 2-OCH₃ H H A038 4-OCH₃ H H A038 4-F H H A039 H H H A039 3-CH₃ H H A039 7-OCH₃ H H A040 H H H A041 H H H A041 H 4-Cl H A041 H 4-CH₃ H A041 H 4-CH₃ CH₃ A041 H 4-CH₃ CH₂Ph A041 H 4-CH₃ C(O)Ph A041 H 4-CH₃ C(O)OEt A041 H 4-t-Bu H A041 H 4-n-hex H A041 H 4-OCH₃ H A041 H 4-Ph H A041 6-NO₂ H H A041 6-Br H H A042 H H H A042 H 4-Cl H A042 H 4-CH₃ H A042 H 4-CH₃ CH₃ A042 H 4-CH₃ CH₂Ph A042 H 4-CH₃ C(O)Ph A042 H 4-CH₃ C(O)OEt A042 H 4-t-Bu H A042 H 4-n-hex H A042 H 4-OCH₃ H A042 H 4-Ph H A042 5-Br H H A043 H H H A044 H H H A051 — H H A052 — H H A053 — H H A054 — H H A055 — H H A056 — H H A057 — H H A058 — H H A059 — H H A060 — H H A061 — H H A062 — H H A063 — H H A064 — H H A065 — H H A066 — H H A067 — H H A068 — H H A101 — H H A102 — H H A103 — H H A104 — H H A105 — H H A106 — H H A107 — H H

TABLE 11 The locants for the substituent R²¹ in the Table correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R²¹ R⁸ (Z)m R³ H c-Pr — H 4-Cl c-Pr — H 4-CH₃ c-Pr — H 4-CH₃ c-Pr — CH₃ 4-CH₃ c-Pr — CH₂Ph 4-CH₃ c-Pr — C(O)Ph 4-CH₃ c-Pr — C(O)OEt 4-t-Bu c-Pr — H 4-n-hex c-Pr — H 4-n-hex c-Pr — CH₃ 4-n-hex c-Pr — CH₂Ph 4-n-hex c-Pr — C(O)Ph 4-n-hex c-Pr — C(O)OEt 4-OCH₃ c-Pr — H 4-Ph c-Pr — H H c-Bu — H H c-Pen — H H c-Hex — H 4-Cl c-Hex — H 4-CH₃ c-Hex — H 4-CH₃ c-Hex — CH₃ 4-CH₃ c-Hex — CH₂Ph 4-CH₃ c-Hex — C(O)Ph 4-CH₃ c-Hex — C(O)OEt 4-t-Bu c-Hex — H 4-n-hex c-Hex — H 4-n-hex c-Hex — CH₃ 4-n-hex c-Hex — CH₂Ph 4-n-hex c-Hex — C(O)Ph 4-n-hex c-Hex — C(O)OEt 4-OCH₃ c-Hex — H 4-Ph c-Hex — H H c-C₇H₁₅ — H H c-C₈H₁₇ — H H bicyclo[2.2.1]heptan-2-yl — H H 1-adamantyl — H H 2-adamantyl — H H A001 H H H A001 3-n-Bu H H A002 H H H A002 2-Cl H H A003 H H H A004 H H H A005 H H 4-Cl A005 H H 4-CH₃ A005 H H 4-CH₃ A005 H CH₃ 4-CH₃ A005 H CH₂Ph 4-CH₃ A005 H C(O)Ph 4-CH₃ A005 H C(O)OEt 4-t-Bu A005 H H 4-n-hex A005 H H 4-n-hex A005 H CH₃ 4-n-hex A005 H CH₂Ph 4-n-hex A005 H C(O)Ph 4-n-hex A005 H C(O)OEt 4-OCH₃ A005 H H 4-Ph A005 H H H A005 2,5-(CH₃)₂ H H A005 2,5-Cl₂ H H A005 2-Br H H A006 H H 4-Cl A006 H H 4-CH₃ A006 H H 4-CH₃ A006 H CH₃ 4-CH₃ A006 H CH₂Ph 4-CH₃ A006 H C(O)Ph 4-CH₃ A006 H C(O)OEt 4-t-Bu A006 H H 4-n-hex A006 H H 4-n-hex A006 H CH₃ 4-n-hex A006 H CH₂Ph 4-n-hex A006 H C(O)Ph 4-n-hex A006 H C(O)OEt 4-OCH₃ A006 H H 4-Ph A006 H H H A006 3-CH₃ H H A006 5-CH₃ H H A006 3-Cl H H A006 5-Et H H A006 5-Cl H H A006 5-Br H H A006 3-Br H H A006 4-Br H H A006 5-NO₂ H H A007 H H H A007 5-CH₃ H H A007 3-CH₃ H H A007 5-Br H H A007 5-NO₂ H H A007 5-Ph H H A008 5-CH₃ H H A009 5-CH₃ H H A010 3,5-(CH₃)₂ H H A010 3,5-Cl₂ H H A011 3,5-(CH₃)₂ H H A011 3,5-Cl₂ H H A012 3-CH₃ H H A012 3-Me H H A012 3-Cl H H A013 3-CH₃ H H A013 3-Me H H A013 3-Cl H H A014 H H 4-Cl A014 H H 4-CH₃ A014 H H 4-CH₃ A014 H CH₃ 4-CH₃ A014 H CH₂Ph 4-CH₃ A014 H C(O)Ph 4-CH₃ A014 H C(O)OEt 4-t-Bu A014 H H 4-n-hex A014 H H 4-OCH₃ A014 H H 4-Ph A014 H H H A015 H H H A016 2,4-(CH₃)₂ H 4-Cl A016 2,4-(CH₃)₂ H 4-CH₃ A016 2,4-(CH₃)₂ H 4-CH₃ A016 2,4-(CH₃)₂ CH₃ 4-CH₃ A016 2,4-(CH₃)₂ CH₂Ph 4-CH₃ A016 2,4-(CH₃)₂ C(O)Ph 4-CH₃ A016 2,4-(CH₃)₂ C(O)OEt 4-t-Bu A016 2,4-(CH₃)₂ H 4-n-hex A016 2,4-(CH₃)₂ H 4-OCH₃ A016 2,4-(CH₃)₂ H 4-Ph A016 2,4-(CH₃)₂ H H A017 2,4-(CH₃)₂ H H A018 H H H A018 3-CH₃ H H A019 3-Ph, 5-CH₃ H H A019 3,5-(CH₃)₂ H H A020 5-CH₃ H H A021 4-CH₃ H H A022 H H H A023 2,4-(CH₃)₂ H H A024 2-(4-pyridil) H H A025 H H H A026 H H H A026 4-CH₃ H H A027 H H H A027 4-CH₃ H H A028 H H H A029 H H H A030 H H H A031 H H H A032 H H H A033 H H H A034 H H H A034 3,6-Cl₂ H H A035 H H H A036 H H H A037 H H 4-Cl A037 H H 4-CH₃ A037 II H 4-CH₃ A037 H CH₃ 4-CH₃ A037 H CH₂Ph 4-CH₃ A037 H C(O)Ph 4-CH₃ A037 H C(O)OEt 4-t-Bu A037 H H 4-n-hex A037 H H 4-n-hex A037 H CH₃ 4-n-hex A037 H CH₂Ph 4-n-hex A037 H C(O)Ph 4-n-hex A037 H C(O)OEt 4-OCH₃ A037 H H 4-Ph A037 H H H A037 6-OCH₃ H H A037 6-Br H H A038 H H 4-Cl A038 H H 4-CH₃ A038 H H 4-CH₃ A038 H CH₃ 4-CH₃ A038 H CH₂Ph 4-CH₃ A038 H C(O)Ph 4-CH₃ A038 H C(O)OEt 4-t-Bu A038 H H 4-n-hex A038 H H 4-n-hex A038 H CH₃ 4-n-hex A038 H CH₂Ph 4-n-hex A038 H C(O)Ph 4-n-hex A038 H C(O)OEt 4-OCH₃ A038 H H 4-Ph A038 H H H A038 2-OCH₃ H H A038 4-OCH₃ H H A038 4-F H H A039 H H H A039 3-CH₃ H H A039 7-OCH₃ H H A040 H H H A041 H H 4-Cl A041 H H 4-CH₃ A041 H H 4-CH₃ A041 H CH₃ 4-CH₃ A041 II CH₂Ph 4-CH₃ A041 H C(O)Ph 4-CH₃ A041 H C(O)OEt 4-t-Bu A041 H H 4-n-hex A041 H H 4-OCH₃ A041 H H 4-Ph A041 H H H A041 6-NO₂ H H A041 6-Br H H A042 H H 4-Cl A042 H H 4-CH₃ A042 H H 4-CH₃ A042 H CH₃ 4-CH₃ A042 H CH₂Ph 4-CH₃ A042 H C(O)Ph 4-CH₃ A042 H C(O)OEt 4-t-Bu A042 H H 4-n-hex A042 H H 4-OCH₃ A042 H H 4-Ph A042 H H H A042 5-Br H H A043 H H 4-Cl A043 H H 4-CH₃ A043 H H 4-CH₃ A043 H CH₃ 4-CH₃ A043 H CH₂Ph 4-CH₃ A043 H C(O)Ph 4-CH₃ A043 H C(O)OEt 4-t-Bu A043 H H 4-n-hex A043 H H 4-OCH₃ A043 H H 4-Ph A043 H H H A044 H H 4-Cl A044 H H 4-CH₃ A044 H H 4-CH₃ A044 H CH₃ 4-CH₃ A044 H CH₂Ph 4-CH₃ A044 H C(O)Ph 4-CH₃ A044 H C(O)OEt 4-t-Bu A044 H H 4-n-hex A044 H H 4-OCH₃ A044 H H 4-Ph A044 H H H A051 — H H A052 — H H A053 — H H A054 — H H A055 — H H A056 — H H A057 — H H A058 — H H A059 — H H A060 — H H A061 — H H A062 — H H A063 — H H A064 — H H A065 — H H A066 — H H A067 — H H A068 — H H A101 — H H A102 — H H A103 — H H A104 — H H A105 — H H A106 — H H A107 — H

TABLE 12

(Z)m (Z)m R² on ring of R² R⁸ on ring of R⁸ R³ H — c-Pr — H CH₃ — c-Pr — H H — c-Bu — H CH₃ — c-Bu — H H — c-Pen — H CH₃ — c-Pen — H H — c-Hex — H CH₃ — c-Hex — H CH₃ — c-Hex — CH₃ CH₃ — c-Hex — CH₂Ph CH₃ — c-Hex — C(O)Ph CH₃ — c-Hex — C(O)OEt C(O)CH₃ — c-Pr — H C(O)CH₃ — c-Hex — H C(O)CH₃ — c-Hex — CH₃ C(O)CH₃ — c-Hex — CH₂Ph C(O)CH₃ — c-Hex — C(O)Ph C(O)CH₃ — c-Hex — C(O)OEt C(O)Ph — c-Pr — H C(O)Ph — c-Hex — H C(O)Ph — c-Hex — CH₃ C(O)Ph — c-Hex — CH₂Ph C(O)Ph — c-Hex — C(O)Ph C(O)Ph — c-Hex — C(O)OEt A005 H A005 H H A005 H A006 H H A005 H A014 H H A005 H A016 2,4-(CH₃)₂ H A005 H A037 H H A005 H A038 H H A005 H A041 H H A005 H A042 H H A005 H A043 H H A005 H A044 H H A006 H A005 H H A006 H A006 H H A006 H A006 H CH₃ A006 H A006 H CH₂Ph A006 H A006 H C(O)Ph A006 H A014 H H A006 H A016 2,4-(CH₃)₂ CH A006 H A037 H H A006 H A037 H CH₃ A006 H A037 H CH₂Ph A006 H A037 H C(O)Ph A006 H A038 H H A006 H A038 H CH₃ A006 H A038 H CH₂Ph A006 H A038 H C(O)Ph A006 H A041 H H A006 H A041 H CH₃ A006 H A041 H CH₂Ph A006 H A041 H C(O)Ph A006 H A042 H H A006 H A042 H CH₃ A006 H A042 H CH₂Ph A006 H A042 H C(O)Ph A006 H A043 H H A006 H A044 H H A014 H A005 H H A014 H A006 H H A014 H A014 H H A014 H A016 2,4-(CH₃)₂ H A014 H A037 H H A014 H A038 H H A014 H A041 H H A014 H A042 H H A014 H A043 H H A014 H A044 H H A016 2,4-(CH₃)₂ A005 H H A016 2,4-(CH₃)₂ A006 H H A016 2,4-(CH₃)₂ A014 H H A016 2,4-(CH₃)₂ A016 2,4-(CH₃)₂ H A016 2,4-(CH₃)₂ A037 H H A016 2,4-(CH₃)₂ A038 H H A016 2,4-(CH₃)₂ A041 H H A016 2,4-(CH₃)₂ A042 H H A016 2,4-(CH₃)₂ A043 H H A016 2,4-(CH₃)₂ A044 H H A036 H A005 H H A036 H A006 H H A036 H A014 H H A036 H A016 2,4-(CH₃)₂ H A036 H A037 H H A036 H A038 H H A036 H A041 H H A036 H A042 H H A036 H A043 H H A036 H A044 H H A037 H A005 H H A037 H A006 H H A037 H A006 H CH₃ A037 H A006 H CH₂Ph A037 H A006 H C(O)Ph A037 H A014 H H A037 H A016 2,4-(CH₃)₂ H A037 H A037 H H A037 H A037 H CH₃ A037 H A037 H CH₂Ph A037 H A037 H C(O)Ph A037 H A038 H H A037 H A038 H CH₃ A037 H A038 H CH₂Ph A037 H A038 H C(O)Ph A037 H A041 H H A037 H A041 H CH₃ A037 H A041 H 1CH₂Ph A037 H A041 H C(O)Ph A037 H A042 H H A037 H A042 H CH₃ A037 H A042 H CH₂Ph A037 H A042 H C(O)Ph A037 H A043 H H A037 H A044 H H A038 H A005 H H A038 H A006 H H A038 H A006 H CH₃ A038 H A006 H CH₂Ph A038 H A006 H C(O)Ph A038 H A014 H H A038 H A016 2,4-(CH₃)₂ H A038 H A037 H H A038 H A037 H CH₃ A038 H A037 H CH₂Ph A038 H A037 H C(O)Ph A038 H A038 H H A038 H A038 H CH₃ A038 H A038 H CH₂Ph A038 H A038 H C(O)Ph A038 H A041 H H A038 H A041 H CH₃ A038 H A041 H CH₂Ph A038 H A041 H C(O)Ph A038 H A042 H H A038 H A042 H CH₃ A038 H A042 H CH₂Ph A038 H A042 H C(O)Ph A038 H A043 H H A038 H A044 H H A041 H A005 H H A041 H A006 H H A041 H A006 H CH₃ A041 H A006 H CH₂Ph A041 H A006 H C(O)Ph A041 H A014 H H A041 H A016 2,4-(CH₃)₂ H A041 H A037 H H A041 H A037 H CH₃ A041 H A037 H CH₂Ph A041 H A037 H C(O)Ph A041 H A038 H H A041 H A038 H CH₃ A041 H A038 H CH₂Ph A041 H A038 H C(O)Ph A041 H A041 H H A041 H A041 H CH₃ A041 H A041 H CH₂Ph A041 H A041 H C(O)Ph A041 H A042 H H A041 H A042 H CH₃ A041 H A042 H CH₂Ph A041 H A042 H C(O)Ph A041 H A043 H H A041 H A044 H H A042 H A005 H H A042 H A006 H H A042 H A006 H CH₃ A042 H A006 H CH₂Ph A042 H A006 H C(O)Ph A042 H A014 H H A042 H A016 2,4-(CH₃)₂ H A042 H A037 H H A042 H A037 H CH₃ A042 H A037 H CH₂Ph A042 H A037 H C(O)Ph A042 H A038 H H A042 H A038 H CH₃ A042 H A038 H CH₂Ph A042 H A038 H C(O)Ph A042 H A041 H H A042 H A041 H CH₃ A042 H A041 H CH₂Ph A042 H A041 H C(O)Ph A042 H A042 H H A042 H A042 H CH₃ A042 H A042 H CH₂Ph A042 H A042 H C(O)Ph A042 H A043 H H A042 H A044 H H The expression — indicates unsubstituted.

TABLE 13 The locants for the substituents R¹¹, R²¹ and R⁸¹ in the Table correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R¹¹ R²¹ R⁸¹ R³ H H H H H 4-CH₃ H H H 4-t-Bu H H H 4-t-Bu 4-CH₃ H H 4-t-Bu H CH₃ H 4-t-Bu 4-CH₃ CH₃ H 4-n-Hex H H H 4-n-Hex 4-Cl H H 4-n-Hex 4-Br H H 4-n-Hex 4-CH₃ H H 4-n-Hex H CH₃ H 4-n-Hex 4-CH₃ CH₃ H 4-n-Hex H CH₂Ph H 4-n-Hex H C(O)OEt H 4-n-Hex H C(O)Ph H 4-Ph H H H 4-Ph 4-CH₃ H H 4-Ph H CH₃ H 4-Ph 4-CH₃ CH₃ 4-F H H H 2-Cl H H H 3-Cl H H H 4-Cl H H H 4-Cl 4-t-Bu H H 4-Cl 4-t-Bu 4-CH₃ H 4-Cl 4-n-Hex H H 4-Cl 4-n-Hex 4-Cl H 4-Cl 4-n-Hex 4-Br H 4-Cl 4-n-Hex 4-CH₃ H 4-Cl 4-Ph H H 4-Cl 4-Ph 4-CH₃ H 4-Br H H H 3,4-Cl₂ H H H 4-NO₃ H H H 4-CN H H H 2-CH₃ H H H 3-CH₃ H H H 4-CH₃ H H H 4-CH₃ 4-t-Bu H H 4-CH₃ 4-t-Bu 4-CH₃ H 4-CH₃ 4-n-Hex H H 4-CH₃ 4-n-Hex 4-Cl H 4-CH₃ 4-n-Hex 4-Br H 4-CH₃ 4-n-Hex 4-CH₃ H 4-CH₃ 4-Ph H H 4-CH₃ 4-Ph 4-CH₃ H 3,4-(CH₃)₂ H H H 4-OCH₃ H H H 4-OCH₃ 4-t-Bu H H 4-OCH₃ 4-n-Hex H H 4-OCH₃ 4-n-Hex 4-Cl H 4-OCH₃ 4-n-Hex 4-Br H 4-OCH₃ 4-n-Hex 4-CH₃ H 4-OCH₃ 4-Ph H H 3,4-(OCH₃) H H H 4-Ph H H H

TABLE 14 The locants for the substituent R⁸¹ herein correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R¹ R² (Z)m R⁸¹ R³ H H — H H Et H — H H n-Pr H — H H n-Bu H — H H c-Bu H — H H n-Pen H — H H c-Pen H — H H CF₃ H — H H CF₃ H — 4-CH₃ H CF₃ H — 4-CH₃ CH₃ CF₃ A005 — H H CF₃ A006 — H H CF₃ A014 H H CF₃ A016 2,4-(CH₃)₂ H H CF₃ A036 H H H CF₃ A037 — H H CF₃ A038 — H H CF₃ A041 — H H CF₃ A042 — H H CN H — H H C(O)OEt H — H H Ph H — H H (4-CH₃)Ph H — H H (4-i-Pr)Ph H — H H (4-OCH₃)Ph H — H H (4-OCH₃)Ph H — 4-CH₃ H

TABLE 15 The locants for the substituents R²¹ and R⁸¹ in the Table correspond to the positions indicated in the following structural formulae, and the expression — indicates unsubstituted.

R¹ (Z)m R²¹ R⁸¹ R³ H — H H H Et — H H H n-Pr — H H H n-Bu — H H H CF₃ — H H H CF₃ — 4-CH₃ H H CF₃ — 4-CH₃ 4-CH₃ H CF₃ — 4-CH₃ 4-CH₃ CH₃ CF₃ — 4-t-Bu H H CF₃ — 4-n-Hex 4-CH₃ H CF₃ — 4-n-Hex 4-CH₃ CH₃ CF₃ — 4-Ph H H CO₂Et — H H H A001 H H H H A002 H H H H A003 H H H H A005 H H H H A005 2,5-(CH₃)₂ H II H A005 2,5-Cl₂ H H H A005 2-Br H H H A006 H H H H A006 3-CH₃ H H H A006 5-CH₃ H H H A006 3-Cl H H H A006 5-Et H H H A006 5-Cl H H H A006 5-Br H H H A006 3-Br H H H A006 4-Br H H H A006 5-NO₂ H H H A007 H H H H A007 5-CH₃ H H H A007 3-CH₃ H H H A007 5-Br H H H A007 5-NO₂ H H H A007 5-Ph H H H A008 5-CH₃ H H H A009 5-CH₃ H H H A010 3,5-(CH₃)₂ H H H A010 3,5-Cl₂ H H H A011 3,5-(CH₃)₂ H H H A011 3,5-Cl₂ H H H A012 3-CH₃ H H H A012 3-CH₃ H H H A012 3-Cl H H H A013 3-CH₃ H H H A013 3-CH₃ H H H A013 3-Cl H H H A014 H H H H A015 H H H H A016 2,4-(CH₃)₂ H H H A017 2,4-(CH₃)₂ H H H A034 H H H H A034 3,6-Cl₂ H H H A035 H H H H A036 H H H H A037 H H H H A037 6-OCH₃ H H H A037 6-Br H H H A038 H H H H A038 2-OCH₂ H H H A038 4-OCH₃ H H H A038 4-F H H H

EXAMPLES

Now, the present invention will be described in further detail with reference to Synthetic Examples and Assay Examples of the compounds of the present invention.

However, it should be understood that the present invention is by no means restricted by these specific Examples.

The compounds obtained in the Synthetic Examples were identified by proton nuclear magnetic resonance (¹H NMR) by chemical shifts relative to tetramethylsilane (Me₄Si) as the standard.

SYNTHETIC EXAMPLES Synthetic Example 1 Synthesis of 4-(4-hexylphenyl)-3-isopropyl-1-(2-methyl-1-p-tolylpropan-2-yl)-1H-pyrazol-5-ol (Compound No. 3-07 of the Present Invention) Step 1 Synthesis of Triphenyl(t-butoxycarbonylimino)phosphorane

25 g (0.19 mol) of t-butylcarbazate was dissolved in 80 mL of acetic acid and 160 mL of water, and 15 g (0.22 mol) of sodium nitrite was added in small portions under cooling with ice. The reaction solution was stirred for 30 minutes under cooling with ice and extracted with 250 ml of diisopropyl ether. The organic layer was washed with 200 mL of saturated aqueous sodium hydrogen carbonate twice and with 100 mL of saturated aqueous sodium chloride once successively, dried over anhydrous sodium sulfate and filtered to give a solution of t-butyl carbonazidate in diethyl ether

To the solution of t-butyl carbonazidate in diethyl ether, 49.6 g (0.189 mol) of triphenylphosphine was added in small portions under cooling with ice, and the reaction solution was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration, washed with 200 mL of hexane and dried under reduced pressure to give 67 g of the desired product as white crystals.

Step 2 Synthesis of t-Butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate

20.0 g (53.0 mol) of triphenyl(t-butoxycarbonylimino)phosphorane was suspended in 80 mL of toluene, mixed with 8.84 g (60.0 mmol) of anhydrous chloral and heated at 120° C. for 4 hours under reflux. After cooling to room temperature, 300 mL of hexane was added, and the resulting white solid was separated by filtration. The filtrate was concentrated under reduced pressure. The resulting brown liquid was dissolved in 200 mL of chloroform, and simultaneous addition of 3.74 g (50.0 mmol) of potassium carbonate in 20 mL of ice-cold water and 4.94 g (15 mmol) of OXONE (2 KHSC₅.KHSC₄.K₂SC₄, supplied from Du Pont) in 40 mL of ice-cold water and 1 hour of stirring under cooling with ice were repeated three times. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE (2 KHSC₅.KHSC₄.K₂SC₄, supplied from Du Pont) and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, 11.2 g (150 mmol) of potassium carbonate in 60 mL of ice-cold water and 14.8 g (45 mmol) of OXONE in 120 mL of ice-cold water were added simultaneously, and the reaction solution was stirred for 1 hour of stirring under cooling with ice. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, the chloroform layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate {100:0 (volume ratio, hereinafter the same applies) to 80:20} as the eluent to give 10.3 g of the desired product as a pale yellow oil.

Step 3 Synthesis of 2-chloro-N-(2-methyl-1-p-tolylpropan-2-yl)acetamide

8.21 g (50 mmol) of 2-methyl-1-p-tolylpropan-2-ol and 12.0 mL of acetic acid were dissolved in 11.3 g (0.15 mol) of chloroacetonitrile, mixed with 12.0 mL (0.15 mol) of sulfuric acid under cooling with ice and stirred at room temperature for 5 hours. The reaction solution was poured into 200 mL of ice-cold water and extracted with diisopropyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 10.8 g of the desired product as white crystals.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.11 (d, J=7.7 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 6.24 (br, 1H), 3.94 (s, 2H), 2.98 (s, 2H). 2.33 (s, 3H), 1.37 (s, 6H)zz

Step 4 Synthesis of 2-methyl-1-p-tolylpropan-2-amine

6.24 g (26.0 mmol) of 2-chloro-N-(2-methyl-1-p-tolylpropan-2-yl)acetamide and 1.98 g (26.0 mmol) of thiourea were dissolved in 50 mL of ethanol, and 10.2 mL of acetic acid was added dropwise at room temperature. After 3 hours of stirring at 85° C. the resulting white suspension was allowed to cool and diluted with 300 mL of water. The reaction solution was basified with 20 wt % aqueous sodium hydroxide and extracted with hexane, and the extract was washed with saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure to give 4.04 g of the desired product as a yellow green liquid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.02-7.13 (m, 4H), 2.61 (s, 2H), 2.33 (s, 3H). 1.18 (br, 2H), 1.16 (s, 6H)

Step 5 Synthesis of t-butyl 2-(2-methyl-1-p-tolylpropan-2-yl)hydrazinecarboxylate

2.40 g (14.7 mmol) of separately prepared 2-methyl-1-p-tolylpropan-2-amine was dissolved in 20 mL of methylene chloride, and 2.60 g (10.0 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate in 10 mL of methylene chloride was added under cooling with ice. The reaction slution was stirred under cooling with ice for 30 minutes and at room temperature for 1 hour, and the methylene chloride was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:0 to 0:100) as the eluent to give 1.61 g of the desired product as colorless crystals.

Step 6 Synthesis of 2-(4-hexylphenyl)-1-morpholinoethanethione

5.0 g (25 mmol) of 1-(4-hexylphenyl)ethanone was dissolved in 2.13 g (24.5 mmol) of morpholine and heated with 1.33 g (41.6 mmol) of sulfur at 115° C. for 5 hours under reflux. After completion of the reaction, the reaction solution was cooled to room temperature and mixed with methanol, and the reaction product precipitated as crystals were collected by filtration, washed and dried to give 4.50 g of the desired product as pale yellow crystals.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.11˜7.26 (m, 4H), 4.3˜4.5 (m, 4H), 3.6˜3.9 (m, 4H) 3.35˜3.48 (m, 2H), 2.55˜2.60 (m, 2H), 1.51-1.70 (m, 2H), 1.23-1.42 (m, 6H), 0.82-1.01 (m, 3H) Step 7; Synthesis of 2-(4-hexylphenyl)acetic acid

12.0 g (39.3 mmol) of 1-(4-hexylphenyl)ethanone was dissolved in 23.6 g (393 mmol) of glacial acetic acid, mixed with 4.95 g (275 mmol) of water and 5.79 g (58.9 mmol) of sulfuric acid and heated at 150° C. for 6.5 hours under reflux. After completion of the reaction, the reaction solution was diluted with 400 mL of water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:20 to 1:4) as the eluent to give 5.74 g of the desired product as white crystals.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.08˜7.21 (m, 4H), 3.61 (s, 2H), 2.55-2.61 (m, 2H), 1.51-1.67 (m, 2H), 1.20-1.41 (m, 6H), 0.86-0.90 (m, 3H) Step 8;

Synthesis of ethyl 2-(4-hexylphenyl)acetate

5.5 g (25 mmol) of 2-(4-hexylphenyl)acetic acid was dissolved in 11 mL of ethanol and mixed with 1.1 g (11.2 mmol) of sulfuric acid and stirred at 60° C. for 1 hour. The reaction was quenched with cold saturated aqueous sodium carbonate (100 ml), and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 5.68 g of the desired product as a pale yellow oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.06˜7.22 (m, 4H), 4.14 (q, J=7.2 Hz, 2H), 3.57 (s, 2H), 2.58 (t, J=7.8 Hz, 2H), 1.50˜1.65 (m, 2H), 1.1-1.4 (m, 6H), 1.25 (t, J=7.2 Hz, 3H), 0.82-0.92 (m, 3H)

Step 9 Synthesis of ethyl 2-(4-hexylphenyl)-4-methyl-3-oxopentanoate

6.0 g (24 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 130 mL of dry tetrahydrofuran under a nitrogen atmosphere and cooled to −60° C. After addition of 31.8 mL (36.2 mmol) of 1.14 M solution of lithiumdiisopropylamine in hexane/tetrahydrofuran, the solution was warmed to 0° C. and stirred for 1 hours. The reactuion solution was cooled to −60° C. again and stirred with 3.6 g (34 mmol) of isobutyryl chloride at −60° C. to room temperature for 15 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (150 ml), and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (0:100 to 1:9) as the eluent to give 5.39 g of the desired product as a pale yellw oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.11˜7.33 (m, 4H), 4.84 (s, 1H), 4.19 (d, J=7.1 Hz, 2H), 2.67˜2.81 (m, 1H), 2.59 (t, J=7.8 Hz, 2H), 1.50˜1.71 (m, 2H), 1.22˜1.42 (m, 6H), 1.27 (d, J=7.1 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H), 0.81˜0.95 (m, 3H)

Step 10 Synthesis of 4-(4-hexylphenyl)-3-isopropyl-1-(2-methyl-1-p-tolylpropan-2-yl)-1H-pyrazol-5-ol (Compound No. 3-07 of the Present Invention)

200 mg (0.72 mmol) of t-butyl 2-(2-phenylpropan-2-yl)hydrazinecarboxylate was dissolved in 3 mL of methylene chloride and stirred with 251 mg (1.3 mmol) of paratoluenesulfonic acid monohydrate at room temperature for 23 hours. The reaction solution was basified with saturated aqueous sodium hydrogen carbonate (50 ml) and separated, and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 0.80 mL of toluene and 35 μL of acetic acid and stirred with 226 mg (0.71 mmol) of separately preprared ethyl 2-(4-hexylphenyl)-4-methyl-3-oxopentanoate at 90° C. for 8 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography using hexane-ethyl acetate (1:20 to 1:3) as the eluent to give 130 mg of the desired product as a pale yellow solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.18˜7.42 (m, 4H), 7.00 (s, 4H), 3.21 (s, 2H), 3.16 (sep, J=7.2 Hz, 1H), 2.61 (t, J=7.5 Hz, 2H), 2.29 (s, 3H), 1.62 (s, 6H), 1.54˜1.58 (m, 2H), 1.26˜1.36 (m, 6H), 1.07 (d, J=7.2 Hz, 6H), 0.87-0.92 (m, 3H)

Synthetic Example 2 Synthesis of 1-(2-methyl-1-phenylpropan-2-yl)-3-phenyl-1H-pyrazol-5(4H)-one (Compound No. 3-16 of the Present Invention) Step 1 Synthesis of 1-(2-methyl-1-phenylpropan-2-yl)-2-(propan-2-ylidene)hydrazine

Acetone azine (1.50 g, 13.4 mmol) was dissolved in 10 mL of diethyl ether, mixed with 32 mL (19.2 mmol) of 0.6 M benzylmagnesium bromide in tetrahydrofuran and stirred at 45° C. for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 ml), and the reaction solution was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (9:1 to 6:1) as the eluent to give 710 mg of the desired product as a pale yellow oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.03˜7.28 (m, 5H), 4.2˜4.4 (m, 1H), 2.78 (s, 2H), 1.99 (s, 3H), 1.62 (s, 3H), 1.18 (s, 6H)

Step 2 Synthesis of 1-(2-methyl-1-phenylpropan-2-yl)-3-phenyl-1H-pyrazol-5(4H)-one (Compound No. 3-16 of the Present Invention)

500 mg (2.45 mmol) of 1-(2-methyl-1-phenylpropan-2-yl)-2-(propan-2-ylidene)hydrazine was dissolved in 3.0 mL of glacial acetic acid, mixed with 429 mg (2.23 mmol) of ethyl 3-oxo-3-phenylpropanoate and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:1 to 9:1) as the eluent to give 330 mg of the desired product as a pale orange solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.12˜7.62 (m, 10H), 3.59 (s, 2H), 3.19 (s, 2H), 1.59 (s, 6H)

Synthetic Example 3 Synthesis of 3-(2-methyl-1-phenylpropan-2-yl)-1-(2-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (Compound No. 3-04 of the Present Invention) Step 1; Synthesis of 2,2-dimethyl-3-phenylpropanoic acid

Hexamethyldisilazane (34 g, 0.21 mol) was dissolved in tetrahydrofuran (280 mL), and 1.67M n-butyllithium in hexane (127 mL, 0.21 mol) was added dropwise at −78° C. The reaction solution was warmed to 0° C. over 1 hour and then cooled to −78° C. again. Benzyl isobutyrate (25 g, 0.14 mol) in tetrahydrofuran (70 mL) was added dropwise, and the reaction solution was stirred at −78° C. for 1 hour. Chlorotrimethylsilane (36 mL, 0.12 mol) was further added dropwise at the same temperature, and the reaction solution was stirred for 1 hour, then warmed to room temperature and stirred for 19 hours. After completion of the reaction, the solvent was partially removed from the reaction solution under reduced pressure, and the resulting white suspension was diluted with hexane (200 mL) and filtered through Celite under a nitrogen atmosphere to remove the white solid from the reaction solution. The filtrate was distiled under reduced pressure, and the resulting pale yellow oil was heated at 100° C. for 2 hours to give a brown oil. The brown oil was mixed with 10 mL of 1 M hydrochloric acid and stirred at 60° C. for 4 hours, neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (100 mL×2) and chloroform (100 mL×2). The resulting organic layer was concentrated, and the resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 80 g, ethyl acetate 100%) to give 8.41 g of the desired product as white crystals.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.20-7.30 (m, 3H), 7.16 (d, J=7.1 Hz, 2H), 2.89 (s, 2H), 1.21 (s, 6H)

Step 2 Synthesis of 2,2-dimethyl-3-phenylpropanoyl chloride

To 2,2-dimethyl-3-phenylpropanoic acid (4.0 g, 0.023 mol) thionyl chloride (2.97 g, 0.025 mol) was added in small portions at room temperature, and the resulting solution was stirred at 70° C. for 3 hours, then at room temperature for another 15 hours. The reaction solution was fractionally distilled (113-115° C., 5 mmHg) to give 2.89 g of the desired product as a colorless liquid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.20-7.30 (m, 3H), 7.18 (d, J=7.1 Hz, 2H), 2.97 (s, 2H), 1.28 (s, 6H)

Step 3 Synthesis of ethyl 4,4-dimethyl-3-oxo-5-phenylpentanoate

Ethyl 3-oxobutanoate (1.09 g, 8.3 mmol) in methylene chloride (16 mL) was mixed with anhydrous magnesium chloride (158 mg, 1.66 mmol), and the reaction solution was cooled to 0° C., mixed with pyridine (1.34 mL, 16.6 mmol), stirred for 30 minutes, then mixed with 2,2-dimethyl-3-phenylpropanoyl chloride (1.64 g, 8.3 mmol) and stirred for another 30 minutes at the same temperature. The reaction solution was warmed to room temperature and stirred for 20 hours. The methylene chloride was distilled off under reduced pressure, and the residue was with ethanol (2 mL) and at room temperature for 2 days and with toluene (2 mL) at 60° C. for 5 hours. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (50 mL×2). The solvent was removed from the resulting organic layer under reduced pressure, and the resulting brown oil was purified by intermediate pressure silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:19 to 1:9) to give 370 mg of the desired product as a light brown oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.18-7.32 (m, 3H), 7.10 (d, J=7.1 Hz, 2H), 4.18 (q, J=7.1 Hz, 3H), 3.46 (s, 2H), 2.83 (s, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.15 (s, 6H)

Step 4 Synthesis of 3-(2-methyl-1-phenylpropan-2-yl)-1-(2-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (Compound No. 3-04 of the Present Invention)

tert-Butyl 2-(2-phenylpropan-2-yl)hydrazinecarboxylate (250 mg, 1.00 mmol) was dissolved in methylene chloride (2 mL), mixed with p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) and stirred at room temperature for 16 hours. After the stirring, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate to terminate the reaction and then separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (3.0 mL) and acetic acid (70 μL), and mixed with ethyl 4,4-dimethyl-3-oxo-5-phenylpentanoate (248 mg, 1.00 mmol) and stirred at 90° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and mixed with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:9 to 3:7) to give 42 mg of the desired product as a brown oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.15-7.34 (m, 8H), 6.98-7.10 (m, 2H), 3.08 (s, 2H), 2.79 (s, 2H)., 1.84 (s, 6H), 1.18 (s, 6H)

Synthetic Example 4 Synthesis of 5-methoxy-3-phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazole (Compound No. 3-13 of the Present Invention) and 5-methoxy-4-methyl-3-phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazole (Compound No. 3-14 of the Present Invention)

3-Phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazol-5-ol (83 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), and 55 wt % sodium hydride (suspended in mineral oil) (26 mg, 0.60 mmol) was added at room temperature. After 1 hour of stirring at room temperature, methyl iodide (18 μL, 0.30 mmol) was added dropwise, and the reaction solution was stirred at the same temperature for 18 hours. The reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (10 mL×2). The organic layer was washed with saturated aqueous sodium chloride (10 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, hexane 100%) to give 35 mg of 5-methoxy-3-phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazole as a colorless solid and 10 mg of 5-methoxy-4-methyl-3-phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazole as a colorless oil, respectively.

-   5-methoxy-3-phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazole

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.83 (d, J=7.4 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.15-7.33 (m, 4H), 7.08 (d, J=7.1 Hz, 2H), 5.91 (s, 1H), 3.60 (s, 3H), 1.98 (s, 6H) 5-methoxy-4-methyl-3-phenyl-1-(2-phenylpropan-2-yl)-1H-pyrazole

¹H NMR (CDCl₃, Me₄Si, 300 MHz)67.73 (d, J=7.4 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.16-7.36 (m, 4H), 3.16 (s, 3H), 2.10 (s, 3H), 1.98 (s, 6H)

Synthetic Example 5 Synthesis of 1-(1-(4-bromophenyl)-2-methylpropan-2-yl)-3-isopropyl-1H-pyrazol-5(4H)-one (Compound No. 3-12 of the Present Invention)

To 1-(2,2-dimethyl-1,1-diphenylpropyl)-2-(propan-2-ylidene)hydrazine (147 mg, 0.500 mmol) in tetrahydrofuran (5 mL), 1.61 M n-butylithium in hexane (0.37 mL, 0.60 mmol) was added dropwise at −78° C., and after 1 hour of stirring at the same temperature, p-bromobenzyl bromide (125 mg, 0.50 mmol) was added dropwise. The reaction solution was stirred at the same temperature for 1 hour, warmed to room temperature and stirred at room temperature for 18 hours. The reaction solution was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (10 mL×3). The resulting organic layer was concentrated under reduced pressure, and the resulting residue was dissolved in 2 mL of ethanol, mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 24 hours. After the stirring, the reaction solution was mixed with concentrated hydrochloric acid (3 mL) and stirred at 80° C. for 5 hours. After the stirring, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (3.0 mL) and acetic acid (70 μL), mixed with methyl isobutyrylacetic acid (72 mg, 0.50 mmol) and stirred at 90° C. for 3 hours. The reaction solution was allowed to cool to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:9 to 3:7) to give 15 mg of the desired product as a brown oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.35 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 3.14 (s, 2H), 3.06 (s, 2H), 2.59 (sep, J=6.8 Hz, 1H), 1.50 (s, 6H), 1.10 (d, J=7.1 Hz, 6H)

Synthetic Example 6 Synthesis of ethyl 5-hydroxy-3-isopropyl-1-(2-phenylpropan-2-yl)-1H-pyrazole-4-carboxylate (Compound No. 4-27 of the Present Invention)

3-Isopropyl-1-(2-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (1.22 g, 5.00 mmol) and calcium hydroxide (435 mg, 7.50 mmol) were suspended in dioxane (20 mL), heated to 45° C. and stirred for 1 hour. After the stirring, the reaction solution was allowed to cool to room temperature, and after dropwise addition of ethyl chloroformate (597 mg, 5.50 mmol), stirred at 90° C. for 6 hours. After completion of the reaction, the resulting light brown suspension was poured into ice-cold 3 M hydrochloric acid and extracted with chloroform (20 mL×5). The resulting organic layer was washed with 0.06 M hydrochloric acid (50 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 40 g, ethyl acetate:hexane=1:19 to 1:9) to give 650 mg of the desired product as a yellow oil.

¹H NMR (CDCl₃, Me_(a) Si, 300 MHz) δ9.71 (s, 1H), 7.13-7.33 (m, 3H)., 7.05-7.12 (m, 2H), 4.31 (q, J=7.1 Hz, 2H), 3.23 (sep, J=6.9 Hz, 1H), 1.94 (s, 6H), 1.36 (t, 7.3 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H)

Synthetic Example 7 Synthesis of methyl 2-(5-oxo-1-(2-phenylpropan-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)acetate (Compound No. 4-01 of the Present Invention)

tert-Butyl 2-(2-phenylpropan-2-yl)hydrazinecarboxylate (250 mg, 1.00 mmol) was dissolved in methylene chloride (2 mL), mixed with p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) and stirred at room temperature for 18 hours. The reaction solution was basified with saturated aqueous sodium hydrogen carbonate and separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in toluene (2.0 mL) and acetic acid (70 μL), mixed with dimethyl 1,3-acetonedicarboxylate (174 mg, 1.00 mmol) and stirred at 90° C. for 3 hours and at 105° C. for 3 hours. After completion of the reaction, the reaction solution was allowed to cool to room temperature and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:9 to 3:7) to give 96.3 mg of the desired product as a white solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.18-7.34 (m, 5H), 3.75 (s, 3H), 3.48 (s, 2H), 3.41 (s, 2H), 1.87 (s, 6H)

Synthetic Example 8 Synthesis of 4-bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (Compound No. 3-47 of the Present Invention)

3-Isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (1.2 g, 4.6 mmol) was dissolved in N,N-dimethylformamide (35 mL), mixed with N,N-bromosuccinimide (908 mg, 5.10 mmol) and stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by suspending in hexane to give 1.26 g of the desired product as a pale blue solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.06-7.29 (m, 5H), 4.64 (s, 1H), 3.12 (d, J=13.4 Hz, 1H), 3.03 (d, J=13.4 Hz, 1H), 2.73-2.88 (m, 1H), 1.53 (s, 3H), 1.52 (s, 3H), 1.16 (d, J=6.9 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H)

Synthetic Example 9 Synthesis of methyl 4-(5-hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)benzoate (Compound No. 4-23 of the Present Invention)

4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5-yl benzoate (360 mg, 0.82 mmol) in 1,2-dimethoxyethane (4.8 ml) was mixed with 4-(methoxycarbonyl)phenylboronic acid (164 mg, 0.911 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol) and 2 M aqueous sodium carbonate (3.6 ml) and stirred at 86° C. for 16 hours under a nitrogen atmosphere. After completion of the reaction, the 1,2-dimethoxyethane was distilled off under reduced pressure, and the reaction solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was purified by intermediate pressure silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20 to 1:4) to give 100 mg of the desired product as a pale yellow solid mixture of tautomers.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ8.0-8.1 (m, 2H), 7.6-7.7 (m, 2H), 7.15-7.3 (m, 3H), 7.05-7.15 (m, 2H), 6.37 (br, 1H), 3.92 (s, 3H), 3.27 (s, 2H), 3.12-3.19 (m, 1H), 1.65 (s, 6H), 1.08 (d, J=7.2 Hz, 6H)

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ8.0-8.1 (m, 2H), 7.6-7.7 (m, 2H), 7.15-7.3 (m, 3H), 7.05-7.15 (m, 2H), 4.2-4.3 (m, 1H), 3.92 (s, 3H), 3.1-3.2 (m, 2H), 2.35-2.5 (m, 1H), 1.65 (s, 6H), 0.95-1.05 (m, 6H)

Synthetic Example 10 Synthesis of (5-hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)(phenyl)methanone (Compound No. 4-71 of the Present Invention) Step 1 Synthesis of 4-bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5-yl benzoate

4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (3.00 g, 8.90 mmol) was dissolved in 39 mL of tetrahydrofuran and cooled with ice to 0° C., and after dropwise addition of 1.80 g (17.8 mmol) of triethylamine and 1.38 g (9.82 mmol) of benzoyl chloride, stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction was quenched with distilled water, and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20) to give 3.34 g of the desired product as a yellow oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.98-8.05 (m, 2H), 7.62-7.70 (m, 1H), 7.44-7.56 (m, 2H), 7.18-7.26 (m, 3H), 6.78-6.88 (m, 2H), 3.07 (s, 2H), 2.92-3.06 (m, 1H), 1.56 (s, 6H), 1.29 (d, J=6.9 Hz, 6H)

Step 2 Synthesis of (5-hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)(phenyl)methanone (Compound No 4-71 of the Present Invention)

1.60 g (3.63 mmol) of 4-bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5-yl benzoate was dissolved in 16 mL of tetrahydrofuran and cooled with a coolant (acetone/dry ice) to −60° C., and after dropwise addition of 2.60 ml (4.24 mmol) of 1.63 M n-butyllithium in n-hexane, stirred at 72° C. for 4 hours under a nitrogen atmoephere. The reaction was quenched with distilled water, and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel12 g, ethyl acetate:hexane=1:20) to give 520 mg of the desired product as a yellow oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.15-7.63 (m, 8H), 6.90-6.98 (m, 2H), 3.17 (s, 2H), 2.60-2.74 (m, 1H), 1.64 (s, 6H), 0.96 (d, J=6.9 Hz, 6H)

Synthetic Example 11 4-(4-Hexylphenyl)-5-hydroxy-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carbonitrile (Compound No. 4-86 of the Present Invention) Step 1 Synthesis of ethyl 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate

152 mg (0.329 mol) of ethyl 4-(4-hexylphenyl)-5-hydroxy-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate was dissolved in 1.6 mL of N,N-dimethylformamide, mixed with 26 mg (0.65 mmol) of 60 wt % sodium hydride (suspended in mineral oil) and 0.050 mL (0.66 mmol) of chloromethyl methyl ether under cooling with ice successively and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with 1 M hydrochloric acid, with saturated aqueous sodium hydrogen carbonateand with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 174 mg).

Step 2 Synthesis of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylic acid

Ethyl 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate (138 mg) was dissolved in 2 mL of tetrahydrofuran and 0.7 mL of methanol, mixed with 0.27 mL (1.4 mmol) of 5 M aqueous sodium hydroxide and stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was diluted with methylene chloride and washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 142 mg).

Step 3 Synthesis of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl-1H-pyrazole-3-carboxamide

4-(4-Hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylic acid (142 mg) was dissolved in 1.4 mL of ethanol and mixed with 125 mg (0.407 mmol) of (4.6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphlinium chloride with a 90% purity. The reaction solution was stirred at room temperature for 30 minutes and stirred with 0.54 mL (1.1 mmol) of 2 M ammonia in ethanol for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give Compound 5 (crude yield 171 mg) as a white amorphous substance.

Step 4 Synthesis of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carbonitrile

171 mg of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxamide was dissolved in 2 mL of methylene chloride and mixed with 0.3 mL (2 mmol) of triethylamine. The reaction solution was cooled to 0° C. in an ice bath, and after dropwise addition of 0.080 mL (0.72 mmol) of trichloroacetyl chloride at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was mixed with methylene chloride and washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 266 mg).

Step 5 Synthesis of 4-(4-hexylphenyl)-5-hydroxy-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carbonitrile (Compound No. 4-86 of the Present Invention)

266 mg of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carbonitrile was dissolved in 4 mL of tetrahydrofuran and 0.8 mL of methanol, mixed with 4 M hydrochloric acid in dioxane (0.70 mL, 2.8 mmol) and stirred at room temperature for 14 hours. After completion of the reaction, the solvent was partly distilled off under reduced pressure, and the crystals precipitated in the reaction mixture were separated by filtration and washed with isopropyl ether. The filtrate was combined with the isopropyl ether washing and concentrated under reduced pressure, and the resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 10 g, ethyl acetate:hexane=0:100 to 20:80) to give 88.1 mg of the desired product as a white solid.

m.p. 140-142° C.

Synthetice Example 12 1-(5-Hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)ethanone O-methyl oxime (Compound No. 4-89 of the Present Invention)

150 mg (0.50 mmol) of 1-(5-hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)ethanone, 209 mg (2.50 mmol) of methoxyamine hydrochloride and 286 mg (3.49 mmol) of sodium acetate were mixed with 1.3 ml of distilled water and 1.3 ml of ethanol and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 4 g, ethyl acetate:hexane=1:99) to give 70 mg of the desired product as an orange oil.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.12-7.22 (m, 3H), 6.84-6.95 (m, 2H), 3.87 (s, 3H), 3.16 (s, 2H), 2.98-3.12 (m, 1H), 2.25 (s, 3H), 1.57 (s, 6H), 1.21 (d, J=6.8 Hz, 6H)

Synthetic Example 13 4-(4-Hexylphenyl)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazol-5-ol (Compound No. 4-90 of the Present Invention) Step 1; Synthesis of ethyl 3-(dimethylamino)-2-(4-hexylphenyl)acrylate

0.50 g (2.0 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 7 mL of N,N-dimethylformamide, mixed with 0.31 mL (2.3 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 18 hours. After the stirring, the reaction mixture was further mixed with 0.65 mL (4.9 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product as a brown liquid.

Step 2 Synthesis of 4-(4-hexylphenyl)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazol-5-ol (Compound No. 4-90 of the Present Invention)

Ethyl 3-(dimethylamino)-2-(4-hexylphenyl)acrylate and 0.50 g (1.8 mmol) of tert-butyl 2-(2-methyl-1-(p-tolyl)propan-2-yl)hydrazinecarboxylate were dissolved in 2 mL of acetic acid and stirred at 90° C. for 24 hours. After the stirring, the reaction mixture was mixed with 0.5 mL of acetic acid and stirred for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with distilled water, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 35:65). The resulting solid was washed with isopropyl ether to give 164 mg of the desired product as a white solid.

m.p. 149-151° C.

Synthetic Example 14 Synthesis of tert-butyl 2-(2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-yl)hydrazinecarboxylate Step 1 Synthesis of 1-(2-azido-2-methylpropyl)-4-(trifluoromethyl)benzene

25 g (0.12 mol) of 4-trifluoromethylphenyl acetate was mixed with 300 mL of ethanol and concentrated sulfuric acid (95%, 5 mL) and stirred at 40° C. for 16 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and the reaction solution was diluted wiht ethyl acetate and washed with distilled water, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 27.9 g of crude ethyl 2-(4-(trifluoromethyl)phenyl)acetate.

27.9 g of ethyl 2-(4-(trifluoromethyl)phenyl)acetate was dissolved in 150 mL of dry tetrahydrofuran, and 280 mL (0.28 mol) of 0.99 M methylmagnesium bromide in tetrahydrofuran was added dropwise under cooling with ice under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours, and after the stirring, the reaction was quenched with distilled water. The organic layer was washed with 1 M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 26.3 g of crude 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol.

26.3 g of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol was dissolved in 400 mL of methylene chloride, and 25 mL (0.19 mol) of trimethylsilyl azide and 24 mL (0.19 mol) of boron trifluoride diethyl ether complex were added dropwise under cooling with ice. The reaction mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 25.4 g of the desired product.

Step 2; Synthesis of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-amine

25.4 g of 1-(2-azido-2-methylpropyl)-4-(trifluoromethyl)benzene was dissolved in 210 mL of ethyl acetate and mixed with 0.84 g of 20 wt % palladium hydroxide carbon. The atmosphere in the reaction vessel was replaced with hydrogen gas, and the reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, the palladium hydroxide carbon was filtered off, and the filtrate was mixed with 3 M hydrochloric acid and separated. The aqueous layer was basified with 5 M sodium hydroxide and extracted with methylene chloride. The organic layer was concentrated under reduced pressure to give 4.27 g of the desired product as a brown liquid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.56 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 2.72 (s, 2H), 1.2-1.5 (m, 2H), 1.32 (s, 6H)

Step 3 Synthesis of tert-butyl 2-(2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-yl)hydrazinecarboxylate

4.2 g of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-amine was dissolved in 30 mL of methylene chloride and mixed with 5.6 g (21 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice. The reaction solution was stirred at room temperature for 30 minutes, washed with 10% aqueous citric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and methylene chloride was removed under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 100 g, ethyl acetate:hexane) to give 1.38 g of the desired product as a white solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.54 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.8-6.0 (m, 1H), 2.74 (s, 2H), 1.46 (s, 9H), 1.4-1.5 (m, 1H), 1.03 (s, 6H)

Synthetic Example 15 Synthesis of tert-butyl 2-(1-benzylcyclopropyl)hydrazinecarboxylate Step 1 Synthesis of 1-benzylcyclopropanamine

4.5 g (38 mmol) of phenylacetonitrile was dissolved in 50 mL of tetrahydrofuran, mixed with 12.4 mL (41.9 mmol) of tetraisopropyl propylorthotitanate and 78 mL (76 mmol) of 0.98M ethylmagnesium bromide in tetrahydrofuran and stirred at room temperature for 1 hour. After the stirring, 9.6 mL (78 mmol) of boron trifluoride ethyl ether complex was added, and the reaction solution was stirred at room temperature for another 1 hour. After completion of the reaction, 2 M aqueous sodium hydroxide was added, and the reaction solution was extracted with diethyl ether. After addition of 3 M hydrochloric acid, the organic layer was separated. The resulting aqueous layer was basified with 5 M aqueous sodium hydroxide and extracted with methylene chloride. The solvent was removed from the organic layer under reduced pressure to give 3.28 g of the desired product.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.2-7.4 (m, 5H), 2.75 (s, 2H), 1.4-1.6 (m, 2H), 0.6-0.7 (m, 4H)

Step 2 Synthesis of tert-butyl 2-(1-benzylcyclopropyl)hydrazinecarboxylate

10.6 g (72.0 mmol) of 1-benzylcyclopropanamine was dissolved in 90 mL of methylene chloride, mixed with 14.3 g (54.5 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice, and stirred at room temperature for 30 minutes. After completion of the reaction, methylene chloride was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel 350 g, ethyl acetate:hexane=1:20) to give 4.6 g of the desired product as a brown solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.2-7.4 (m, 5H), 5.8-6.0 (m, 1H), 3.9-4.2 (m, 1H), 2.87 (s, 2H), 1.45 (s, 9H), 0.75-0.85 (m, 2H), 0.5-0.55 (m, 2H)

Synthetic Example 16 Synthesis of tert-butyl 2-(3-benzylpentan-3-yl)hydrazinecarboxylate Step 1 Synthesis of 3-benzylpentan-3-amine

3.0 g (26 mmol) of phenylacetonitrile was dissolved in 50 mL of tetrahydrofuran and mixed with 8.3 mL (28 mmol) fo titanium isopropoxide, and 115 mL (104 mmol) of 0.90 Methylmagnesium bromide in tetrahydrofuran was added dropwise under a nitrogen atmosphere. After 1 hour of stirring, the reaction was quenched by adding water dropwise under cooling with ice. The reaction mixture was diluted with ethyl acetate and separated. After addition of 1 M hydrochloric acid, the organic layer was separated. The aqueous layer was basified with 5 M aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride layer was concentrated under reduced pressure to give the desired product (crude yield 2.68 g).

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.1-7.5 (m, 5H), 2.64 (s, 2H), 1.2-1.5 (m, 6H), 0.91 (t, J=7.5 Hz, 6H)

Step 2 Synthesis of tert-butyl 2-(3-benzylpentan-3-yl)hydrazinecarboxylate

2.68 g of 3-benzylpentan-3-amine was dissolved in 20 mL of methylene chloride, mixed with 4.8 g (18 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice and stirred at room temperature for 30 mitues, and the reaction solution was washed with 10% aquoeous citric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and methylene chloride was removed under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 20:80) to give 1.62 g of the desired product as a light brown solid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ7.1-7.4 (m, 5H), 5.5-5.7 (br, 1H), 3.6-3.8 (Br, 1H), 2.66 (s, 2H), 1.55 (s, 9H), 1.3-1.5 (m, 4H), 0.93 (t, J=7.5 Hz, 6H)

Synthetic Example 17 Synthesis of ethyl 2-(furan-2-yl)-4-methyl-3-oxopentanoate Step 1 Synthesis of 2-(furan-2-yl)acetic acid

25 g (0.25 mmol) of furfuryl alcohol was dissloved in 250 mL of tetrahydrofuran, mixed with 8.7 mL of phosphorus tribromide under cooling with ice and stirred at the same temperature for 90 minutes. After completion of the reaction, the reaction solution was diluted with diethyl ether and washed with distilled water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude 2-(bromomethyl)furan.

2-(Bromomethyl)furan was dissolved in 125 mL of N,N-dimethylformaide, mixed with 13.7 g (0.280 mmol) of sodium cyanide and stirred at room temperature for 11 hours. After the stirring, the reaction solution was mixed with 100 mL of N,N-dimethylformamide and 13.7 g (0.280 mmol) of sodium cyanide and stirred for another 8 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether and washed with distilled water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude 2-(furan-2-yl)acetonitrile.

2-(Furan-2-yl)acetonitrile was suspended in 300 mL of distilled water, mixed with 50 g (0.89 mmol) of potassium hydroxide and heated for 4 hours under reflux. After completion of the reaction, the reaction solution was diluted with diethyl ether and separated. The resulting aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filterd, and the filtrate was concentrated under reduced pressure to give 25.2 g of the desired product.

Step 2 Synthesis of ethyl 2-(furan-2-yl)acetate

24.8 g of 2-(furan-2-yl)acetic acid was dissolved in 590 mL of N,N-dimethylformamide and mixed with 32.6 g (0.236 mol) of potassium carbonate and 6.42 g (19.7 mmol) cesium carbonate successively. The reaction mixture was further mixed with 19 mL (0.24 mol) of iodoethane under cooling with ice and stirred at room temperature for 14 hours. After completion of the reaction, the reaction mixture was diluted with distilled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 17.0 g of the desired product as a brown liquid.

Step 3; Synthesis of ethyl 2-(furan-2-yl)-4-methyl-3-oxopentanoate

To 60 mL of tetrahydrofuran and 9.3 mL (66 mmol) of diisopropylamine, 38 mL (60 mmol) of 1.57 M n-butyllithium in n-hexane was added dropwise under a nitrogen atmosphere under cooling with ice, and the reaction mixture was warmed to room temperature and stirred for 30 minutes. After the stirring, the reaction mixture was cooled to −78° C., and after dropwise addition of 4.62 g (30.0 mmol) of ethyl 2-(furan-2-yl)acetate, stirred at the same temperature for 1 hour. After the stirring, 3.8 mL (36 mmol) of isobutyryl chloride was added at −78° C., and the reaction mixture was gradually warmed and then stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with saturated aqueous ammonium chloride under cooling with ice and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=1:10) to give 22 g of the desired product as an orange liquid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ13.5 (s, 1H), 7.4-7.5 (m, 1H), 6.35-6.45 (m, 1H), 6.1-6.2 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 2.4-2.6 (m, 1H), 1.22 (t, J=7.1 Hz, 3H), 1.11 (d, J=6.9 Hz, 6H)

Synthetic Example 18 Synthesis of O-hexylhydroxylamine Step 1 Synthesis of 2-(hexyloxy)isoindoline-1,3-dione

3.0 g (18 mmol) of N-hydroxysuccinimide was dissolved in 30 mL of N,N-dimethylformamide, mixed with 0.81 g (20 mmol) of 60 wt % sodium hydride (dispersed in mineral oil) under cooling with ice and stirred at room temperature for 30 minutes. After the stirring, 2.8 mL (20 mmol) of bromohexane and 35 mg (0.23 mmol) of sodium iodide were added dropwise successively under cooling with ice, and the reaction mixture was stirred at 70° C. for 20 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water, and the solid precipitated in the reaction mixture was collected by filtration and dried to give 5.82 g of the desired product as a white solid.

Step 2 Synthesis of O-hexylhydroxylamine

5.82 g of 2-(hexyloxy)isoindoline-1,3-dione was dissolved in 95 mL of methanol, mixed with 3.0 mL (62 mmol) of hydrazine monohydrate and stirred at 65° C. for 30 minutes. After completion of the reaction, the solid precipitated in the reaction mixture was collected by filtration and washed with methylene chloride. The filtrate was combined with the methylene chloride washings and concentrated under reduced pressure and distilled by simple distillation (column top 110° C.) to give a mixture of the desired product and hydrazine. The mixture was diluted with diethyl ether, washed with distilled water, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 0.76 g of the desired product as a colorless liquid.

¹H NMR (CDCl₃, Me₄Si, 300 MHz) δ5.84 (s, 2H), 3.49 (t, J=6.6 Hz, 3H), 1.4-1.6 (m, 2H), 1.2-1.4 (m, 6H), 0.86 (t, J=6.6 Hz, 3H)

The compounds of the present invention other than those mentioned above can be obtained in accordance with the previously mentioned processes and the Examples. Compounds obtained in the same manners as in Synthetic Examples 1 and 2 are listed in Tables 16 to 20 together with those obtained in the Examples. However, the present invention is not restricted thereto.

In the Tables, Et denotes ethyl group, and similarly, n-Pr and Pr-n denote normal propyl group, i-Pr and Pr—I denote isopropyl group, c-Pr and Pr-c denote cyclopropyl group, n-Bu and Bu-n denote normal butyl group, s-Bu and Bu-s denote secondary butyl group, i-Bu and Bu—I denote isobutyl group, t-Bu and Bu-t denote t-butyl group, c-Bu and Bu-c denote cyclobutyl group, n-Pen and Pen-n denote normal pentyl group, c-Pen and Pen-c denote cyclopentyl group, n-Hex and Hex-n denote normal hexyl group, c-Hex and Hex-c denote cyclohexyl group, and Ph denotes phenyl group.

In Table 16, Table 17, Table 18, Table 19 and Table 20, “No.” means the numbers by which compounds of the present invention are designated.

TABLE 16

No. R¹ R² R³ R⁸¹ 1-01 CH₃ H H H 1-02 CH₃ CH₃ H H 1-03 CH₃ n-Hex H H 1-04 CH₃ PhCH₂ H H 1-06 Ph Ph H H 1-07 n-Pr Ph H H 1-11 CH₃ Ph H H 3-01 4-(OCH₃)Ph H H H 3-02 i-Pr H H H 3-03 Ph H H H 3-04 1,1-(CH₃)₂-2-Ph—Et H H H 3-08 i-Pr (4-n-Hex)Ph H H 3-13 Ph H CH₃ H 3-14 Ph CH₃ CH₃ H 3-27 c-Pr (4-n-Hex)Ph H H 3-28 i-Pr (4-n-Hex)Ph H 4-Cl 3-29 c-Pr (4-n-Hex)Ph H 4-Cl 3-30 (4-Ph)Ph (4-n-Hex)Ph H 4-Cl 3-31 (4-Ph)Ph n-Hex H 4-Cl 3-32 (4-t-Bu)Ph (4-n-Hex)Ph H 4-Cl 4-01 CH₂C(O)OCH₃ H H H 4-12 i-Pr n-Pr H H 4-13 (4-Ph)Ph (4-n-Hex)Ph H H 4-14 (4-Ph)Ph n-Hex H H 4-15 (4-t-Bu)Ph (4-n-Hex)Ph H H 4-16 (4-t-Bu)Ph n-Hex H H 4-17 (4-t-Bu)Ph n-Hex H 4-Cl 4-27 i-Pr C(O)OEt H H

TABLE 17

No. R¹ R² R³ R⁸¹ 1-12 CH₃ Ph H H 2-01 CH₃ H H H 2-02 CH₃ CH₃ H H 2-03 CH₃ n-Hex H H 2-04 CH₃ PhCH₂ H H 2-05 CF₃ Ph H H 2-06 Ph Ph H H 2-07 n-Pr Ph H H 2-09 i-Pr Ph H H 2-10 c-Pr Ph H H 2-12 n-Bu Ph H H 2-14 (4-CH₃)Ph Ph H H 2-15 (4-Cl)Ph Ph H H 2-16 (3,4-(OCH₃)₂)Ph Ph H H 2-18 pyridin-2-yl Ph H H 2-19 CH₃ (4-CH₃)Ph H H 2-20 CH₃ (2-CH₃)Ph H H 2-21 CH₃ {3,4-(CH₃)₂}Ph H H 2-22 CH₃ (4-Ph)Ph H H 2-23 CH₃ (4-t-Bu)Ph H H 2-24 CH₃ naphthalen-1-yl H H 2-25 CH₃ (4-n-Hex)Ph H H 2-28 CH₃ (4-OCH₃)Ph H H 2-29 CH₃ benzo[d][1,3]dioxol-5-yl H H 2-30 CH₃ {4-O(CH₂)₂OEt}Ph H H 2-31 CH₃ (4-Cl)Ph H H 2-32 CH₃ (3,4-Cl₂)Ph H H 2-33 CH₃ thiophen-2-yl H H 2-34 i-Pr (4-CH₃)Ph H H 2-35 i-Pr (2-CH₃)Ph H H 2-36 i-Pr {3,4-(CH₃)₂}Ph H H 2-37 i-Pr (4-Ph)Ph H H 2-38 i-Pr (4-t-Bu)Ph H H 2-39 i-Pr naphthalen-1-yl H H 2-40 i-Pr (4-n-Hex)Ph H H 2-43 i-Pr (4-OCH₃)Ph H H 2-44 i-Pr benzo[d][1,3]dioxol-5-yl H H 2-45 i-Pr {4-O(CH₂)₂OEt}Ph H H 2-46 i-Pr (4-Cl)Ph H H 2-47 i-Pr (3,4-Cl₂)Ph H H 2-48 i-Pr thiophen-2-yl H H 2-49 CH₃ (4-CF₃)Ph H H 2-50 i-Pr (4-CF₃)Ph H H 3-05 i-Pr H H 4-CH₃ 3-06 (4-OCH₃)Ph H H 4-CH₃ 3-07 i-Pr (4-n-Hex)Ph H 4-CH₃ 3-09 CF₃ H H 4-CH₃ 3-10 1,1-(CH₃)₂-2-Ph—Et H H 4-CH₃ 3-11 Ph H H 4-CH₃ 3-12 i-Pr H H 4-Br 3-16 Ph H H H 3-17 i-Pr H H H 3-18 i-Pr (4-n-Hex)Ph H 2-CH₃ 3-19 i-Pr H H 3-CH₃ 3-20 i-Pr (4-n-Hex)Ph H 3-CH₃ 3-21 i-Pr (4-n-Hex)Ph PhC(O) 3-CH₃ 3-22 i-Pr H H 4-t-Bu 3-23 i-Pr (4-n-Hex)Ph PhC(O) 4-t-Bu 3-33 i-Pr (4-n-Hex)Ph H 4-Cl 3-34 c-Pr (4-n-Hex)Ph H 4-Cl 3-35 i-Pr n-Pr H 4-Cl 3-36 (4-Ph)Ph (4-n-Hex)Ph H 4-Cl 3-37 (4-t-Bu)Ph (4-n-Hex)Ph H 4-Cl 3-38 i-Pr (4-n-Hex)Ph H 4-OCH₃ 3-39 c-Pr (4-n-Hex)Ph H 4-OCH₃ 3-40 (4-Ph)Ph (4-n-Hex)Ph H 4-OCH₃ 3-41 (4-t-Bu)Ph (4-n-Hex)Ph H 4-OCH₃ 3-43 i-Pr H PhC(O) 4-t-Bu 3-44 i-Pr n-Pr H H 3-45 (4-t-Bu)Ph n-Hex H H 3-46 i-Pr Br H 3-CH₃ 3-47 i-Pr Br H H 3-48 i-Pr (4-n-Hex)Ph H 4-n-Hex 3-49 i-Pr H PhC(O) H 4-03 i-Pr (4-n-Hex)Ph CH₃ 4-n-Hex 4-18 (4-Ph)Ph n-Hex H 4-Cl 4-19 (4-t-Bu)Ph n-Hex H 4-Cl 4-20 (4-Ph)Ph n-Hex H 4-OCH₃ 4-21 (4-t-Bu)Ph n-Hex H 4-OCH₃ 4-22 i-Pr n-Pr H 4-OCH₃ 4-23 i-Pr (4-C(O)OMe)Ph CH₃ H 4-56 i-Pr (4-n-C₈H₁₇)Ph H 4-CH₃ 4-57 i-Pr (4-c-Hex)Ph H 4-CH₃ 4-58 i-Pr furan-2-yl H 4-CH₃ 4-59 n-Hex (4-n-Hex)Ph H 4-CH₃ 4-60 c-Hex (4-n-Hex)Ph H 4-CH₃ 4-61 furan-2-yl (4-n-Hex)Ph H 4-CH₃ 4-62 i-Pr (4-n-Hex)Ph H C(O)OEt 4-71 i-Pr C(O)Ph H H 4-72 (2,4-F₂)Ph (4-n-Hex)Ph H 4-CH₃ 4-73 C(O)OEt (4-n-Hex)Ph H 4-CH₃ 4-74 i-Pr (4-n-Hex)Ph H 4-CF₃ 4-75 (2,4-F₂)Ph (4-n-Hex)Ph H 4-CF₃ 4-76 C(O)OEt (4-n-Hex)Ph H 4-CF₃ 4-83 i-Pr (4-n-Hex)Ph H 2,4-F₂ 4-84 (2,4-F₂)Ph (4-n-Hex)Ph H 2,4-F₂ 4-85 C(O)OEt (4-n-Hex)Ph H 2,4-F₂ 4-86 CN (4-n-Hex)Ph H 4-CH₃ 4-88 i-Pr C(O)CH₃ H H 4-89 i-Pr C(NOCH₃)CH₃ H H 4-90 H (4-n-Hex)Ph H 4-CH₃ 4-91 i-Pr C(NO-n-Hex)CH₃ H H

TABLE 18

No. R¹ R² R³ R⁶ R⁷ R⁸¹ 3-24 i-Pr H H CH₃ H H 3-25 i-Pr (4-n-Hex)Ph H CH₃ H H

TABLE 19

No. R¹ R² R³ R⁸ 4-28 i-Pr (4-n-Hex)Ph H naphthalen-1-yl 4-29 i-Pr (4-n-C₈H₁₇)Ph H naphthalen-1-yl 4-30 i-Pr (4-c-Hex)Ph H naphthalen-1-yl 4-31 i-Pr furan-2-yl H naphthalen-1-yl 4-32 n-Hex (4-n-Hex)Ph H naphthalen-1-yl 4-33 c-Hex (4-n-Hex)Ph H naphthalen-1-yl 4-34 furan-2-yl (4-n-Hex)Ph H naphthalen-1-yl 4-35 i-Pr (4-n-Hex)Ph H thiophen-2-yl 4-36 i-Pr (4-n-C₈H₁₇)Ph H thiophen-2-yl 4-37 i-Pr (4-c-Hex)Ph H thiophen-2-yl 4-38 i-Pr furan-2-yl H thiophen-2-yl 4-39 n-Hex (4-n-Hex)Ph H thiophen-2-yl 4-40 c-Hex (4-n-Hex)Ph H thiophen-2-yl 4-41 furan-2-yl (4-n-Hex)Ph H thiophen-2-yl 4-42 i-Pr (4-n-Hex)Ph H 1-adamantyl 4-43 i-Pr (4-n-C₈H₁₇)Ph H 1-adamantyl 4-44 i-Pr (4-c-Hex)Ph H 1-adamantyl 4-45 i-Pr furan-2-yl H 1-adamantyl 4-46 n-Hex (4-n-Hex)Ph H 1-adamantyl 4-47 c-Hex (4-n-Hex)Ph H 1-adamantyl 4-48 furan-2-yl (4-n-Hex)Ph H 1-adamantyl 4-80 i-Pr (4-n-Hex)Ph H 2,3-dihydro-1H-inden-5-yl 4-81 (2,4-F₂)Ph (4-n-Hex)Ph H 2,3-dihydro-1H-inden-5-yl 4-82 C(O)OEt (4-n-Hex)Ph H 2,3-dihydro-1H-inden-5-yl

TABLE 20

No. R¹ R² R³ R⁴ R⁵ 4-49 i-Pr (4-n-Hex)Ph H —CH₂CH₂— 4-50 i-Pr (4-n-Oct)Ph H —CH₂CH₂— 4-51 i-Pr (4-c-Hex)Ph H —CH₂CH₂— 4-52 i-Pr furan-2-yl H —CH₂CH₂— 4-53 n-Hex (4-n-Hex)Ph H —CH₂CH₂— 4-54 c-Hex (4-n-Hex)Ph H —CH₂CH₂— 4-55 furan-2-yl (4-n-Hex)Ph H —CH₂CH₂— 4-87 i-Pr (4-n-Hex)Ph H C₂H₅ C₂H₅

Next, the physical properties such as proton nuclear magnetic resonance (1H NMR) chemical shifts or melting points of the compounds listed in Tables 16 to 20 are shown in Table 21.

As compounds having a hydrogen atom as R³ are known to have a tautomeric structure P-1, P-2 or P-3 depending on the ¹H NMR measuring conditions, for these compounds, the ¹H NMR measuring conditions, the structures of the tautomers and the mixing ratio of the tautomers, in the case of tautomeric mixtures, are shown in Table 21 as well as the physical properties.

¹H NMR was measured by using tetramethylsilane (Me₄Si) as the standard under the following conditions (i)˜(iii).

(i); solvent CDCl₃, 300 MHz. (ii); solvent DMSO-d₆, 300 MHz. (iii); solvent DMSO-d₆, 400 MHz.

TABLE 21 measuring No. conditions tautomers mixing ratio ¹H NMR chemical shift or melting point 1-01 (i) P-2 δ 7.2-7.4 (m, 5H), 3.22 (s, 2H), 2.07 (s, 3H), 1.87 (s, 6H) 1-02 (i) P-2 δ 7.2-7.4 (m, 5H), 3.00 (q, J = 8.0 Hz, 1H), 2.03 (s, 3H), 1.91 (s, 6H), 1.30 (d, J = 7.7 Hz, 3H) 1-03 (ii) mixture of P-1 

 P-3 6:4 δ 9.33 (s, 1H), 6.8-7.5 (m, 5H), 2.1-2.3 (m, 2H), 2.03 (s, 3H), 1.80 (s, 6H), 1.1-1.4 (m, 8H), 0.8-0.9 (m, 3H) δ 9.4-9.5 (br, 1H), 6.8-7.5 (m, 5H), 2.1-2.3 (m, 2H), 2.03 (s, 3H), 1.74 (s, 6H), 1.1-1.4 (m, 8H), 0.8-0.9 (m, 3H) 1-04 (i) P-2 δ 6.8-7.4 (m, 10H), 2.9-3.7 (m, 3H), 1.4-2.2 (m, 9H) 1-06 (ii) P-1 δ 9.89 (s, 1H), 7.0-7.5 (m, 15H), 1.96 (s, 6H) 1-07 (ii) mixture of P-1 and P-3 7:3 δ 9.66 (s, 1H), 6.9-7.6 (m, 10H), 2.5-2.6 (m, 2H), 1.8-2.0 (m, 6H), 1.4-1.7 (m, 2H), 0.8-1.0 (m, 3H) δ 10.27 (s, 1H), 6.9-7.6 (m, 10H), 2.6-2.7 (m, 2H), 1.8-2.0 (m, 6H), 1.4-1.7 (m, 2H), 0.8-1.0 (m, 3H) 1-11 m.p. 224~225° C. 1-12 m.p. 188~189° C. 2-01 (i) P-2 δ 7.1-7.3 (m, 5H), 3.17 (s, 2H), 3.11 (s, 2H), 2.01 (s, 3H), 1.50 (s, 6H) 2-02 (i) P-2 δ 7.0-7.3 (m, 5H), 2.8-3.3 (m, 3H), 1.2-2.1 (m, 12H) 2-03 (i) P-2 δ 7.0-7.3 (m, 5H), 3.19 (d, J = 13.2 Hz, 1H), 3.06 (d, J = 13.2 Hz, 1H), 2.97 (t, J = 5.7 Hz, 1H), 1.98 (s, 3H), 1.49 (s, 6H), 0.8-1.4 (m, 13H) 2-04 (iii) mixture of P-1 and P-3 5:5 δ 10.04 (s, 1H), 7.0-7.4 (m, 8H), 6.8-6.9 (m, 2H), 3.67 (s, 2H), 3.15 (s, 2H), 1.77 (s, 3H), 1.48 (s, 6H) δ 9.43 (s, 1H), 7.0-7.4 (m, 8H), 6.8-6.9 (m, 2H), 3.46 (s, 2H), 3.21 (s, 2H), 1.90 (s, 3H),, 1.40 (s, 6H) 2-05 (ii) P-1 δ 10.96 (s, 1H), 7.3-7.6 (m, 5H), 7.1-7.3 (m, 3H), 6.9-7.0 (m, 2H), 3.23 (s, 2H), 1.59 (s, 6H) 2-06 (ii) P-1 δ 10.14 (s, 1H), 7.1-7.5 (m, 13H), 6.9-7.1 (m, 2H), 3.24 (s, 2H), 1.61 (s, 6H) 2-07 (ii) mixture of P-1 and P-3 5:5 δ 9.89 (s, 1H), 6.8-7.6 (m, 10H), 3.26 (s, 2H), 2.3-2.5 (m, 2H), 1.52 (s, 6H), 1.3-1.5 (m, 2H), 0.7-0.9 (m, 3H) δ 9.84 (s, 1H), 6.8-7.6 (m, 10H), 3.17 (s, 2H), 2.3-2.5 (m, 2H), 1.49 (s, 6H), 1.3-1.5 (m, 2H), 0.7-0.9 (m, 3H) 2-09 (ii) mixture of P-1 and P-3 7:3 δ 9.79 (s, 1H), 7.3-7.5 (m, 4H), 7.1-7.3 (m, 4H), 6.8-6.9 (m, 2H), 3.14 (s, 2H), 2.87 (sep, J = 6.9 Hz, 1H), 1.53 (s, 6H), 1.02 (d, J = 6.8 Hz, 6H) δ 9.39 (s, 1H), 7.3-7.5 (m, 4H), 7.1-7.3 (m, 4H), 7.0-7.1 (m, 2H), 3.20 (s, 2H), 2.8-3.1 (m, 1H), 1.53 (s, 6H), 1.06 (d, J = 7.1 Hz, 6H) 2-10 (ii) mixture of P-1 and P-3 7:3 δ 9.95 (s, 1H), 7.51 (d, J = 6.9 Hz, 2H), 7.3-7.5 (m, 3H), 7.1-7.3 (m, 3H), 6.8-6.9 (m, 2H), 3.14 (s, 2H), 1.6-1.8 (m, 1H), 1.49 (s, 6H), 0.6-0.7 (m, 4H) δ 9.19 (s, 1H), 7.75 (d, J = 7.4 Hz, 2H), 7.3-7.5 (m, 3H), 7.1-7.3 (m, 3H), 7.0-7.1 (m, 2H), 3.21 (s, 2H), 1.8-2.0 (m, 1H), 1.46 (s, 6H) 0.8-0.9 (m, 4H) 2-12 (ii) mixture of P-1 and P-3 5:5 δ 9.90 (s, 1H), 6.8-7.6 (m, 10H), 3.25 (s, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.52 (s, 6H),, 1.1-1.5 (m, 4H), 0.7-0.9 (m, 3H) δ 9.84 (s, 1H), 6.8-7.6 (m, 10H), 3.17 (s, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.49 (s, 6H), 1.1-1.5 (m, 4H), 0.7-0.9 (m, 3H) 2-14 (ii) P-1 δ 9.9-10.2 (br, 1H), 6.9-7.4 (m, 14H), 3.24 (s, 2H), 2.24 (s, 3H), 1.59 (s, 6H) 2-15 (ii) P-1 δ 10.25 (s, 1H), 7.1-7.5 (m, 12H), 6.9-7.1 (m, 2H), 3.24 (s, 2H), 1.60 (s, 6H) 2-16 (ii) P-1 δ 10.11 (s, 1H), 6.6-7.4 (m, 13H), 3.71 (s, 3H), 3.48 (s, 3H), 3.24 (s, 2H), 1.59 (s, 6H) 2-18 (ii) P-1 δ 10.22 (s, 1H), 8.36 (d, J = 4.7 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.1-7.4 (m, 9H), 6.99 (d, J = 7.7 Hz, 2H) 3.27 (s, 2H), 1.61 (s, 6H) 2-19 (ii) mixture of P-1 and P-3 5:5 δ 9.97 (s, 1H), 6.9-7.6 (m, 9H), 3.19 (s, 2H), 2.31 (s, 3H), 2.04 (s, 3H), 1.46 (s, 6H) δ 9.89 (s, 1H), 6.9-7.6 (m, 9H), 3.28 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 1.46 (s, 6H) 2-20 (ii) mixture of P-1 and P-3 6:4 δ 9.97 (s, 1H), 7.1-7.3 (m, 7H), 6.9-7.0 (m, 2H), 3.0-3.4 (m, 2H), 2.19 (s, 3H),, 1.79 (s, 3H), 1.51 (s, 6H) δ 9.83 (s, 1H), 7.1-7.3 (m, 7H), 6.9-7.0 (m, 2H), 3.0-3.4 (m, 2H), 2.26 (s, 3H), 1.89 (s, 3H), 1.45 (s, 6H) 2-21 (ii) mixture of P-1 and P-3 5:5 δ 9.84 (s, 1H), 7.41 (s, 1H), 7.0-7.3 (m, 6H), 6.95 (d, J = 7.1 Hz, 2H), 3.28 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 2.15 (s, 3H), 1.44 (s, 6H) δ 9.94 (s, 1H), 7.41 (s, 1H), 7.0-7.3 (m, 6H), 6.95 (d, J = 7.1 Hz, 2H), 3.18 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.50 (s, 6H), 2-22 (ii) mixture of P-1 and P-3 6:4 δ 10.08 (s, 1H), 6.9-7.8 (m, 14H), 3.31 (s, 2H), 2.24 (s, 3H), 1.48 (s, 6H) δ 10.15 (s, 1H), 6.9-7.8 (m, 14H), 3.21 (s, 2H), 2.11 (s, 3H), 1.53 (s, 6H) 2-23 (ii) mixture of P-1 and P-3 6:4 δ 9.88 (s, 1H), 6.9-7.6 (m, 9H), 3.28 (s, 2H), 2.16 (s, 3H), 1.45 (s, 6H), 1.30 (s, 18H) δ 9.97 (s, 1H), 6.9-7.6 (m, 9H), 3.18 (s, 2H), 2.05 (s, 3H), 1.50 (s, 6H), 1.30 (s, 18H) 2-24 (ii) mixture of P-1 and P-3 7:3 δ 10.00 (s, 1H), 6.9-8.0 (m, 12H), 3.29 (d, J = 14.0 Hz, 1H), 3.13 (d, J = 12.7 Hz, 1H), 1.77 (s, 3H), 1.58 (s, 6H) δ 10.06 (s, 1H), 6.9-8.0 (m, 12H), 3.1-3.4 (m, 2H), 1.90 (s, 3H), 1.52 (s, 6H) 2-25 (ii) mixture of P-1 and P-3 6:4 δ 9.88 (s, 1H), 6.9-7.7 (m, 9H), 3.29 (s, 2H), 3.57 (t, J = 7.5 Hz, 2H), 2.16 (s, 3H), 1.4-1.7 (m, 8H), 1.30 (s, 6H), 0.8-1.0 (m, 3H) δ 9.96 (s, 1H), 6.9-7.7 (m, 9H), 3.18 (s, 2H), 3.57 (t, J = 7.5 Hz, 2H), 2.04 (s, 3H), 1.4-1.7 (m, 8H), 1.30 (s, 6H), 0.8-1.0 (m, 3H) 2-28 (ii) mixture of P-1 and P-3 5:5 δ 9.90 (s, 1H), 6.9-7.6 (m, 9H), 3.76 (s, 3H), 3.19 (s, 2H), 2.03 (s, 3H), 1.45 (s, 6H) δ 9.80 (s, 1H), 6.9-7.6 (m, 9H), 3.76 (s, 3H), 3.28 (s, 2H), 2.13 (s, 3H), 1.45 (s, 6H) 2-29 (ii) mixture of P-1 and P-3 5:5 δ 9.94 (s, 1H), 6.8-7.4 (m, 8H), 6.00 (s, 2H), 3.27 (s, 2H), 2.15 (s, 3H), 2.04 (s, 3H), 1.44 (s, 6H) δ 9.89 (s, 1H), 6.8-7.4 (m, 8H), 6.01 (s, 2H), 3.17 (s, 2H), 2.02 (s, 3H), 2.04 (s, 3H), 1.49 (s, 6H) 2-30 (ii) mixture of P-1 and P-3 6:4 δ 9.80 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H) 7.1-7.4 (m, 5H), 6.9-7.1 (m, 2H), 4.0-4.2 (m, 2H), 3.6-3.8 (m, 2H), 3.51 (q, J = 7.0 Hz, 2H), 3.29 (s, 2H), 2.14 (s, 3H), 1.44 (s, 6H), 1.14 (t, J = 7.0 Hz, 6H) δ 9.90 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H) 7.1-7.4 (m, 5H), 6.9-7.1 (m, 2H), 4.0-4.2 (m, 2H), 3.6-3.8 (m, 2H), 3.51 (q, J = 7.0 Hz, 2H), 3.19 (s, 2H), 2.02 (s, 3H), 1.50 (s, 6H), 1.14 (t, J = 7.0 Hz, 3H) 2-31 (ii) mixture of P-1 and P-3 7:3 δ 10.16 (s, 1H), 6.9-7.8 (m, 9H), 3.29 (s, 2H), 2.19 (s, 3H), 1.46 (s, 6H) δ 10.16 (s, 1H), 6.9-7.8 (m, 9H), 3.18 (s, 2H), 2.06 (s, 3H), 1.51 (s, 6H) 2-32 (ii) mixture of P-1 and P-3 7:3 δ 10.4-10.5 (m, 1H), 6.8-8.2 (m, 8H), 3.1-3.4 (m, 2H), 2.1-2.4 (m, 3H), 1.48 (s, 6H) δ 10.3-10.4 (m, 1H), 6.8-8.2 (m, 8H), 3.1-3.4 (m, 2H), 2.0-2.2 (m, 3H), 1.48 (s, 6H) 2-33 (ii) mixture of P-1 and P-3 8:2 δ 10.3 (s, 1H), 6.9-7.5 (m, 8H), 3.28 (s, 2H), 2.26 (s, 3H), 1.45 (s, 6H) δ 10.2 (s, 1H), 6.9-7.5 (m, 8H), 3.18 (s, 2H), 2.12 (s, 3H), 1.50 (s, 6H) 2-34 (ii) mixture of P-1 and P-3 8:2 δ 9.73 (s, 1H), 7.1-7.4 (m, 7H), 6.8-6.9 (m, 2H), 3.13 (s, 2H), 2.84 (sep, J = 7.1 Hz, 1H), 2.31 (s, 3H), 1.52 (s, 6H), 1.01 (d, J = 6.9 Hz, 6H) δ 9.31 (s, 1H), 7.1-7.4 (m, 7H), 7.0-7.1 (m, 2H), 3.20 (s, 2H), 2.9-3.1 (m, 1H), 2.31 (s, 3H), 1.52 (s, 6H), 1.05 (d, J = 6.9 Hz, 6H) 2-35 (ii) mixture of P-1 and P-3 8:2 δ 9.76 (s, 1H), 7.1-7.3 (m, 7H), 6.8-6.9 (m, 2H), 3.21 (d, J = 12.7 Hz, 1H), 3.06 (d, J = 13.2 Hz, 1H), 2.4-2.6 (m, 1H), 2.18 (s, 3H), 1.51 (s, 6H), 0.95 (d, J = 6.9 Hz, 3H) δ 9.41 (s, 1H), 7.1-7.3 (m, 7H), 7.0-7.1 (m, 2H), 3.1-3.4 (m, 2H), 2.4-2.6 (m, 1H), 2.22 (s, 3H), 1.55 (s, 6H), 0.86 (d, J = 6.9 Hz, 3H) 2-36 (ii) mixture of P-1 and P-3 7:3 δ 9.70 (s, 1H), 6.8-7.3 (m, 8H), 3.14 (s, 2H), 2.85 (sep, J = 7.7 Hz, 1H), 2.23 (s, 3H), 2.22 (s, 3H), 1.52 (s, 6H), 1.01 (d, J = 6.9 Hz, 6H) δ 9.28 (s, 1H), 6.8-7.3 (m, 8H), 3.20 (s, 2H), 2.9-3.1 (m, 1H), 2.24 (s, 3H), 2.22 (s, 3H), 1.51 (s, 6H), 1.05 (d, J = 7.1 Hz, 6H) 2-37 (ii) mixture of P-1 and P-3 7:3 δ 9.91 (s, 1H), 6.8-7.8 (m, 14H), 3.16 (s, 2H), 2.93 (sep, J = 6.9 Hz, 1H), 1.54 (s, 6H), 1.06 (d, J = 6.9 Hz, 6H) δ 9.48 (s, 1H), 6.8-7.8 (m, 14H), 3.22 (s, 2H), 3.0-3.1 (m, 1H), 1.54 (s, 6H), 1.10 (d, J = 7.1 Hz, 6H) 2-38 (ii) mixture of P-1 and P-3 8:2 δ 9.7-9.8 (m, 1H), 7.1-7.5 (m, 7H), 6.8-6.9 (m, 2H), 3.13 (s, 2H), 2.8-2.9 (m, 1H), 1.52 (s, 6H), 1.31 (s, 9H), 1.03 (d, J = 6.6 Hz, 6H) δ 9.3-9.4 (m, 1H), 7.1-7.5 (m, 7H), 7.0-7.1 (m, 2H), 3.2-3.3 (m, 2H), 2.9-3.1 (m, 1H), 1.52 (s, 6H), 1.31 (s, 9H), 1.03 (d, J = 6.6 Hz, 6H) 2-39 (ii) mixture of P-1 and P-3 8:2 δ 9.76 (s, 1H), 7.2-8.1 (m, 10H), 6.9-7.0 (m, 2H), 3.1-3.3 (m, 2H), 2.4-2.8 (m, 1H), 1.60 (s, 6H), 0.87 (d, J = 6.9 Hz, 6H) δ 9.6-9.7 (m, 1H), 7.2-8.1 (m, 10H), 7.14 (d, J = 8.0 Hz, 2H), 3.1-3.3 (m, 2H), 2.4-2.8 (m, 1H), 1.55 (s, 6H), 0.96 (d, J = 6.6 Hz, 6H) 2-40 (ii) mixture of P-1 and P-3 6:4 δ 9.72 (s, 1H), 7.1-7.4 (m, 7H), 6.8-6.9 (m, 2H), 3.14 (s, 2H), 2.85 (sep, J = 5.5 Hz, 1H), 2.57 (t, J = 6.7 Hz, 2H), 1.52 (s, 6H), 1.5-1.7 (m, 2H), 1.2-1.4 (m, 6H), 1.0-1.2 (m, 6H), 0.8-1.0 (m, 3H) δ 9.3-9.4 (m, 1H), 7.1-7.4 (m, 7H), 7.0-7.1 (m, 2H), 3.19 (s, 2H), 2.9-3.1 (m, 1H), 2.57 (t, J = 6.7 Hz, 1H), 1.52 (s, 6H), 1.5-1.7 (m, 2H), 1.2-1.4 (m, 6H), 1.0-1.2 (m, 6H), 0.8-1.0 (m, 3H) 2-43 (ii) mixture of P-1 and P-3 7:3 δ 9.68 (s, 1H), 6.8-7.4 (m, 9H), 3.77 (s, 3H), 3.13 (s, 2H), 2.82 (sep, J = 6.6 Hz, 1H), 1.52 (s, 6H), 1.01 (d, J = 6.8 Hz, 6H) δ 9.27 (s, 1H), 6.8-7.4 (m, 9H), 3.77 (s, 3H), 3.20 (s, 2H), 2.9-3.1 (m, 1H), 1.52 (s, 6H), 1.05 (d, J = 7.0 Hz, 6H) 2-44 (ii) mixture of P-1 and P-3 7:3 δ 9.73 (s, 1H), 6.7-7.5 (m, 8H), 6.02 (s 2H), 3.12 (s, 2H), 2.83 (sep, J = 6.8 Hz, 1H), 1.51 (s, 6H), 1.01 (d, J = 6.8 Hz, 6H) δ 9.33 (s, 1H), 6.7-7.5 (m, 8H), 6.02 (s 2H), 3.19 (s, 2H), 2.9-3.1 (m, 1H), 1.51 (s, 6H), 1.0-1.2 (m, 6H) 2-45 (ii) mixture of P-1 and P-3 7:3 δ 9.68 (s, 1H), 6.8-7.4 (m, 9H), 4.0-4.2 (m, 2H), 3.6-3.8 (m, 2H), 3.51 (q, J = 6.9 Hz, 2H), 3.13 (s, 2H), 2.82 (sep, J = 6.9 Hz, 1H), 1.52 (s, 6H), 1.14 (t, J = 6.9 Hz, 3H), 1.00 (d, J = 6.9 Hz, 6H) δ 9.27 (s, 1H), 6.8-7.4 (m, 9H), 4.0-4.2 (m, 2H), 3.6-3.8 (m, 2H), 3.51 (q, J = 6.9 Hz, 2H), 3.20 (s, 2H), 2.94 (sep, J = 8.8 Hz, 1H), 1.52 (s, 6H), 1.14 (t, J = 6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 6H) 2-46 (ii) mixture of P-1 and P-3 7:3 δ 9.91 (s, 1H), 7.1-7.5 (m, 7H), 6.8-6.9 (m, 2H), 3.36 (s, 3H), 3.13 (s, 2H), 2.8-2.95 (m, 1H), 1.52 (s, 6H), 1.02 (d, J = 6.9 Hz, 6H) δ 9.55 (s, 1H), 7.1-7.5 (m, 7H), 7.0-7.1 (m, 2H), 3.31 (s, 3H), 3.20 (s, 2H), 2.95-3.1 (m, 1H), 1.52 (s, 6H), 1.06 (d, J = 6.9 Hz, 6H) 2-47 (ii) P-1 δ 10.0-10.2 (br, 1H), 7.4-7.8 (m, 2H), 7.1-7.4 (m, 4H), 6.8-7.1 (m, 2H), 3.15 (s, 2H), 2.8-3.1 (m, 1H), 1.53 (s, 6H), 1.05 (d, J = 6.6 Hz, 6H) 2-48 (ii) mixture of P-1 and P-3 6:4 δ 10.05 (s, 1H), 6.8-7.5 (m, 8H), 3.14 (s, 2H), 2.8-3.1 (m, 1H), 1.51 (s, 6H), 1.08 (d, J = 6.6 Hz, 6H) δ 9.61 (s, 1H), 6.8-7.5 (m, 8H), 3.22 (s, 2H), 2.8-3.1 (m, 1H), 1.51 (s, 6H), 1.13 (d, J = 6.8 Hz, 6H) 2-49 (ii) mixture of P-1 and P-3 7:3 δ 10.41 (s, 1H), 6.9-8.1 (m, 9H), 3.29 (s, 2H), 2.24 (s, 3H), 1.49 (s, 6H) δ 10.3-10.4 (br, 1H), 6.9-8.1 (m, 9H), 3.1-3.4 (m, 2H), 2.12 (s, 3H), 1.49 (s, 6H) 2-50 (ii) mixture of P-1 and P-3 8:2 δ 10.09 (s, 1H), 6.8-7.9 (m, 9H), 3.15 (s, 2H), 2.8-3.0 (m, 1H), 1.54 (s, 6H), 1.05 (s, 6H) δ 9.7-9.8 (br, 1H), 6.8-7.9 (m, 9H), 3.1-3.3 (m, 2H), 3.0-3.1 (m, 1H), 1.54 (s, 6H), 1.03 (s, 6H) 3-01 (i) P-2 δ 7.60 (dd, J = 6.8, 2.1 Hz, 2H), 7.20-7.30 (m, 5H), 6.91 (dd, J = 6.8, 2.4 Hz, 2H), 3.8 (s, 3H), 3.60 (s, 2H), 1.94 (s, 6H) 3-02 (i) P-2 δ 7.15-7.35 (m. 5H), 3.20 (s, 2H), 2.68 (sep, J = 6.8 Hz, 1H), 1.86 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H) 3-03 (i) P-2 δ 7.62-7.70 (m, 2H), 7.20-7.45 (m, 8H), 3.63 (s, 2H), 1.95 (s, 6H) 3-04 (i) P-2 δ 7.15-7.34 (m, 8H), 6.98-7.10 (m, 2H), 3.08 (s, 2H), 2.79 (s, 2H)., 1.84 (s, 6H), 1.18 (s, 6H) 3-05 (i) P-2 δ 7.04 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 3.13 (s, 2H), 3.05 (s, 2H), 2.59 (sep, J = 6.8 Hz, 1H), 2.30 (s, 3H), 1.50 (s, 6H), 1.09 (d, 6.8 Hz, 6H) 3-06 (i) P-2 δ 7.55 (dd, J = 6.8, 2.1 Hz, 2H), 7.03 (s, 4H), 6.91 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 3.14 (s, 2H), 3.56 (s, 2H), 2.28 (s, 3H), 1.56 (s, 6H) 3-07 (i) P-2 δ 7.18~7.42 (m, 4H), 7.00 (s, 4H), 3.21 (s, 2H), 3.16 (sep, J = 7.2 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.62 (s, 6H), 1.54~1.58 (m, 2H), 1.26~1.36 (m, 6H), 1.07 (d, J = 7.2 Hz, 6H), 0.87~0.92 (m, 3H) 3-08 (i) P-2 δ 6.91~7.42 (m, 9H), 3.22 (sep, J = 7.2 Hz, 1H), 2.4~2.7 (m, 2H), 1.55 (s, 6H), 1.53~1.57 (m, 2H), 1.23~1.35 (m, 6H), 1.12 (d, J = 7.2 Hz, 6H), 0.8~0.9 (m, 3H) 3-09 m.p. 144.6~145.5° C. 3-10 (i) P-2 δ 6.91-7.33 (m, 9H), 3.06 (s, 2H), 3.05 (s, 2H), 2.73 (s, 2H), 2.31 (s, 3H), 1.49 (s, 6H), 1.10 (s, 6H) 3-11 (i) P-2 δ 7.55-7.66 (m, 2H), 7.25-7.42 (m, 3H), 7.03 (s, 4H), 3.58 (s, 2H), 3.14 (s, 2H), 2.28 (s, 3H), 1.58 (s, 6H) 3-12 (i) P-2 δ 7.35 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 3.14 (s, 2H), 3.06 (s, 2H), 2.59 (sep, J = 6.8 Hz, 1H), 1.50 (s, 6H), 1.10 (d, J = 7.1 Hz, 6H) 3-13 (i) P-1 δ 7.83 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.15-7.33 (m, 4H), 7.08 (d, J = 7.1 Hz, 2H), 5.91 (s, 1H), 3.60 (s, 3H), 1.98 (s, 6H) 3-14 (i) P-1 δ 7.73 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.16-7.36 (m, 4H), 3.16 (s, 3H), 2.10 (s, 3H), 1.98 (s, 6H) 3-16 (i) P-2 δ 7.12~7.62 (m, 10H), 3.59 (s, 2H), 3.19 (s, 2H), 1.59 (s, 6H) 3-17 (i) P-2 δ 7.09-7.25 (m, 5H), 3.13 (s, 2H), 3.09 (s, 2H), 2.58 (sep, J = 7.2 Hz, 1H), 1.52 (s, 6H), 1.09 (d, J = 6.9 Hz, 6H) 3-18 (i) mixture of P-1 and P-2 4:6 δ 6.94-7.46 (m, 8H), 6.17 (br, 1H), 3.18 (s, 2H), 3.13-3.17 (m, 1H), 2.55-2.66 (m, 2H), 2.35 (s, 3H), 1.64 (s, 6H), 1.50-1.64 (m, 2H), 1.11 (d, J = 6.9 Hz, 6H), 0.95-1.20 (m, 6H), 0.75-0.95 (m, 3H) δ 6.94-7.46 (m, 8H), 4.17 (s, 1H), 3.30 (s, 2H), 2.55-2.66 (m, 2H), 2.40-2.60 (m, 1H), 2.36 (s, 3H), 1.55 (s, 6H), 1.50-1.64 (m, 2H), 1.11 (d, J = 7.2 Hz, 6H), 0.95-1.20 (m, 6H), 0.75-0.95 (m, 3H) 3-19 (i) P-2 δ 7.25-7.15 (m, 1H), 6.95-7.05 (m, 1H), 6.85-7.05 (m, 2H), 3.13 (s, 2H), 3.05 (s, 2H), 2.59 (sep, J = 7.2 Hz, 1H), 2.29 (s, 3H), 1.51 (s, 6H), 1.09 (d, J = 6.9 Hz, 6H) 3-20 (i) mixture of P-1 and P-2 5:5 δ 6.88-7.47 (m, 8H), 6.14 (br, 1H), 3.21 (s, 2H), 3.13-3.20 (m, 1H), 2.52-2.65 (m, 2H), 2.26 (s, 3H), 1.64 (s, 6H), 1.49-1.63 (m, 2H), 1.21-1.39 (m, 6H), 0.95-1.05 (m, 6H), 0.82-0.93 (m, 3H) δ 6.88-7.47 (m, 8H), 4.12 (s, 1H), 2.52-2.65 (m, 2H), 2.40-2.55 (m, 1H), 2.30 (s, 3H), 1.55 (s, 6H), 1.49-1.63 (m, 2H), 1.21-1.39 (m, 6H), 1.05-1.15 (m, 6H), 0.82-0.93 (m, 3H) 3-21 (i) P-1 7.95-8.0 (m, 2H), 7.6-7.7 (m, 1H), 7.45-7.55 (m, 2H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 1H), 6.6-6.7 (m, 1H), 6.56 (s, 1H), 66.03 (s, 1H), 3.09 (s, 2H), 2.92 (sep, J = 6.9 Hz, 1H), 2.22 (s, 3H), 1.64 (s, 6H), 1.25 (d, J 6.9 Hz, 6H) 3-22 (i) P-2 δ 7.2-7.3 (m, 2H), 7.0-7.1 (m, 2H), 3.14 (s, 2H), 3.06 (s, 2H), 2.50-2.65 (m, 1H), 1.52 (s, 6H), 1.29 (s, 9H), 1.08 (d, J 6.9 Hz, 6H) 3-23 (i) mixture of P-1 and P-2 5:5 δ 6.90-7.47 (m, 8H), 6.13 (br, 1H), 3.20 (s, 2H), 3.05-3.19 (m, 1H), 2.52-2.67 (m, 2H), 1.65 (s, 6H), 1.52-1.63 (m, 2H), 1.22-1.41 (m, 6H), 1.27 (s, 9H), 0.94-1.09 (m, 6H), 0.83-0.93 (m, 3H) δ 6.90-7.47 (m, 8H), 4.13 (s, 1H), 3.05-3.19 (m, 2H), 2.52-2.67 (m, 2H), 2.39-2.51 (m, 1H), 1.65 (s, 6H), 1.52-1.63 (m, 2H), 1.22-1.41 (m, 6H), 1.31 (s, 9H), 0.94-1.09 (m, 6H), 0.83-0.93 (m, 3H) 3-24 (i) P-2 δ 7.12-7.30 (m, 5H), 3.63 (d, J = 7.2 Hz, 1H), 3.10 (s, 2H), 2.50-2.65 (m, 1H), 1.56 (s, 3H), 1.40 (s, 3H), 1.26 (d, J = 7.2 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 1.56 (d, J = 6.9 Hz, 3H) 3-25 (i) mixture of P-1 and P-2 5:5 δ 6.88-7.45 (m, 9H), 6.07 (br, 1H), 3.93-4.06 (m, 1H), 3.11 (sep, J = 7.2 Hz, 1H), 2.52-2.65 (m, 2H), 1.81-1.20 (m, 8H), 1.59 (s, 6H), 0.83-1.20 (m, 12H) δ 6.88-7.45 (m, 9H), 4.11 (s, 1H), 3.68-3.77 (m, 1H), 2.52-2.65 (m, 2H), 2.35-2.52 (m, 1H), 1.81-1.20 (m, 8H), 1.59 (s, 6H), 0.83-1.20 (m, 12H) 3-27 (ii) mixture of P-1 and P-3 9:1 δ 9.63 (s, 1H), 7.36 (d, J = 7.7 Hz, 2H), 7.05-7.3 (m, 5H), 6.98 (d, J = 7.4 Hz, 2H), 2.45-2.6 (m, 2H), 1.84 (s, 6H), 1.7-1.9 (m, 1H), 1.45-1.65 (m, 2H), 1.2-1.35 (m, 6H), 0.7-1.05 (m, 7H) δ 9.45-9.55 (br, 1H), 7.5-7.6 (m, 2H), 7.05-7.3 (m, 5H), 6.98 (d, J = 7.4 Hz, 2H), 2.45-2.6 (m, 2H), 1.84 (s, 6H), 1.7-1.9 (m, 1H), 1.45-1.65 (m, 2H), 1.2-1.35 (m, 6H), 0.7-1.05 (m, 7H) 3-28 (ii) mixture of P-1 and P-3 1:9 δ 9.7-9.8 (br, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.1-7.3 (m, 4H), 7.00 (d, J = 8.5 Hz, 2H), 3.05-3.2 (m, 1H), 2.4-2.6 (m, 2H), 1.82 (s, 6H), 1.5-1.6 (m, 2H), 1.2-1.35 (m, 6H), 1.14 (d, J = 6.8 Hz, 6H), 0.75-0.9 (m, 3H) δ 9.56 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.1-7.3 (m, 4H), 7.00 (d, J = 8.5 Hz, 2H), 2.95-3.05 (m, 1H), 2.4-2.6 (m, 2H), 1.87 (s, 6H), 1.5-1.6 (m, 2H), 1.2-1.35 (m, 6H), 1.14 (d, J = 6.8 Hz, 6H), 0.75-0.9 (m, 3H) 3-29 (ii) mixture of P-1 and P-3 9:1 δ 9.67 (s, 1H), 7.3-7.4 (m, 4H), 7.17 (d, J = 7.5 Hz 2H), 7.00 (d, J = 8.5 Hz, 2H), 2.4-2.6 (m, 2H), 1.7-1.9 (m, 1H) 1.83 (s, 6H), 1.45-1.65 (m, 2H), 1.2-1.35 (m, 6H), 0.7-1.1 (m, 7H) δ 9.45-9.55 (br, 1H), 7.5-7.6 (m, 2H), 7.3-7.4 (m, 2H), 7.17 (d, J = 7.5 Hz 2H), 7.00 (d, J = 8.5 Hz, 2H), 2.4-2.6 (m, 2H), 1.7-1.9 (m, 1H) 1.83 (s, 6H), 1.45-1.65 (m, 2H), 1.2-1.35 (m, 6H), 0.7-1.1 (m, 7H) 3-30 (ii) P-1 δ 9.88 (br, 1H), 7.66 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.3-7.55 (m, 7H), 7.1-7.2 (m, 6H), 2.4-2.6 (m, 2H), 1.96 (s, 6H), 1.5-1.65 (m, 2H), 1.2-1.4 (m, 6H), 0.85 (t, J = 6.9 Hz, 3H) 3-31 (ii) P-1 δ 9.70 (s, 1H), 7.65-8.05 (m, 6H), 7.0-7.6 (m, 7H), 2.4-2.55 (m, 2H), 1.91 (s, 6H), 1.3-1.55 (m, 2H), 1.1-1.3 (m, 6H), 0.7-0.9 (m, 3H) 3-32 (ii) P-1 δ 9.80 (s, 1H), 7.25-7.4 (m, 6H), 7.05-7.15 (m, 6H), 2.45-2.6 (m, 2H), 1.93 (s, 6H), 1.45-1.65 (m, 2H), 1.2-1.35 (m, 6H), 1.26 (s, 9H), 0.8-0.9 (m, 3H) 3-33 (ii) mixture of P-1 and P-3 7:3 δ 9.75 (s, 1H), 7.15-7.4 (m, 6H) 6.83 (d, J = 8.4 Hz, 2H), 3.12 (s, 2H), 2.84 (sep, J = 6.8 Hz, 1H), 2.57 (t, J = 7.5 Hz 2H), 1.53 (s, 6H), 1.4-1.65 (m, 2H), 1.2-1.4 (m, 6H), 1.00 (d, J = 6.8 Hz, 6H), 0.8-0.9 (m, 3H) δ 9.31 (s, 1H), 7.15-7.4 (m, 6H) 7.05 (d, J = 8.3 Hz, 2H), 3.20 (s, 2H), 2.9-3.05 (m, 1H), 2.57 (t, J = 7.5 Hz 2H), 1.51 (s, 6H), 1.4-1.65 (m, 2H), 1.2-1.4 (m, 6H), 1.05 (d, J = 7.1 Hz, 6H), 0.8-0.9 (m, 3H) 3-34 (ii) mixture of P-1 and P-3 7:3 δ 9.88 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.15-7.3 (m, 4H), 6.85 (d, J = 8.3 Hz, 2H), 3.12 (s, 2H), 2.57 (t, J = 7.4 Hz, 2H), 1.65-1.75 (m, 1H), 1.55-1.65 (m, 2H), 1.49 (s, 6H), 1.2-1.4 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H), 0.55-0.75 (m, 4H) δ 9.06 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.15-7.3 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 3.22 (s, 2H), 2.57 (t, J = 7.4 Hz, 2H), 1.65-1.75 (m, 1H), 1.55-1.65 (m, 2H), 1.43 (s, 6H), 1.2-1.4 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H), 0.55-0.75 (m, 4H) 3-35 (ii) mixture of P-1 and P-3 6:4 δ 9.51 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.2 Hz, 2H), 3.06 (s, 2H), 2.69 (sep, J = 6.9 Hz, 1H), 2.15-2.3 (m, 2H), 1.46 (s, 6H), 1.4-1.6 (m, 2H), 1.05 (d, J = 6.9 Hz, 6H), 0.88 (t, J = 7.1 Hz, 3H) δ 8.78 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 3.16 (s, 2H), 2.69 (sep, J = 6.9 Hz, 1H),, 2.05-2.15 (m, 2H), 1.42 (s, 6H), 1.4-1.6 (m, 2H), 1.05 (d, J = 6.9 Hz, 6H), 0.88 (t, J = 7.1 Hz, 3H) 3-36 (ii) P-1 δ 10.14 (s, 1H), 7.63 (d, J = 7.7 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.1-7.5 (m, 11H), 6.97 (d, J = 8.2 Hz, 2H), 3.24 (s, 2H), 2.45-2.65 (m, 2H), 1.61 (s, 6H), 1.5-1.65 (m, 2H), 1.2-1.4 (m, 6H), 0.8-0.9 (m, 3H) 3-37 (ii) mixture of P-1 and P-3 9:1 δ 10.04 (s, 1H), 7.0-7.65 (m, 10H), 6.94 (d, J = 8.5 Hz, 2H), 3.21 (s, 2H), 2.45-2.65 (m, 2H), 1.59 (s, 6H), 1.45-1.6 (m, 2H), 1.2-1.35 (m, 6H), 1.22 (s, 9H), 0.8-0.95 (m, 3H) δ 9.85-9.95 (m, 1H), 6.9-7.65 (m, 10H), 3.21 (s, 2H), 2.45-2.65 (m, 2H), 1.59 (s, 6H), 1.45-1.6 (m, 2H), 1.2-1.35 (m, 6H), 1.23 (s, 9H), 0.8-0.95 (m, 3H) 3-38 (ii) mixture of P-1 and P-3 8:2 δ 9.66 (s, 1H), 7.1-7.25 (m, 4H) 6.76 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.2 Hz, 2H), 3.68 (s, 3H), 3.06 (s, 2H), 2.75-2.9 (m, 1H), 2.57 (t, J = 7.4 Hz, 2H), 1.5-1.65 (m, 2H), 1.50 (s, 6H), 1.2-1.4 (m, 6H), 1.02 (d, J = 6.9 Hz, 6H), 0.87 (t J = 6.9 Hz, 3H) δ 9.25-9.35 (br, 1H), 7.25-7.35 (m, 4H), 6.85-6.95 (m, 4H), 3.68 (s, 3H), 3.12 (s, 2H), 2.9-3.05 (m, 1H), 2.57 (t, J = 7.4 Hz 2H), 1.5-1.65 (m, 2H), 1.50 (s, 6H), 1.2-1.4 (m, 6H), 1.07 (d, J = 7.1 Hz, 6H), 0.87 (t J = 6.9 Hz, 3H) 3-39 (ii) P-2 δ 7.4-7.55 (m, 2H) 7.20 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 3.69 (s, 3H), 3.08 (s, 2H), 2.5-2.6 (m, 2H), 1.65-1.8 (m, 1H), 1.55-1.65 (m, 2H), 1.45 (s, 6H), 1.2-1.4 (m, 6H), 0.8-1.0 (m, 3H), 0.7-0.8 (m, 2H), 0.6-0.7 (m, 2H) 3-40 (ii) P-1 δ 10.0-10.1 (m, 1H), 7.75 (d, J = 8.5 Hz, 2H), 6.85-7.7 (m, 13H), 6.76 (d, J = 8.8 Hz, 2H), 3.71 (s, 3H), 3.05-3.25 (m, 2H), 2.45-2.65 (m, 2H), 1.45-1.65 (m, 8H), 1.15-1.35 (m, 6H), 0.8-0.9 (m, 3H) 3-41 (ii) mixture of P-1 and P-3 7:3 δ 10.85 (s, 1H), 6.75-7.3 (m, 12H), 3.73 (s, 3H), 3.05-3.25 (m, 2H), 2.45-2.65 (m, 2H), 1.56 (s, 6H), 1.4-1.65 (m, 2H), 1.2-1.4 (m, 6H), 1.24 (s, 9H), 0.8-0.9 (m, 3H) δ 9.9-10.0 (m, 1H), 6.75-7.65 (m, 12H), 3.67 (s, 3H), 3.05-3.25 (m, 2H), 2.45-2.65 (m, 2H), 1.56 (s, 6H), 1.4-1.65 (m, 2H), 1.2-1.4 (m, 6H), 1.24 (s, 9H), 0.8-0.9 (m, 3H) 3-43 (i) P-1 δ 7.9-8.0 (m, 2H), 7.6-7.7 (m, 1H), 7.45-7.55 (m, 2H), 7.20 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.2 Hz, 1H), 6.04 (s, 1H), 3.10 (s, 2H), 2.83-3.00 (m, 1H), 1.64 (s, 6H), 1.25 (s, 9H), 1.24 (d, J = 7.2 Hz, 6H) 3-44 (i) mixture of P-1 and P-2 1:9 δ 7.01-7.40 (m, 5H), 5.84 (br, 1H), 3.0-3.25 (m, 2H), 2.75-2.91 (m, 1H), 2.2-2.3 (m, 2H), 1.52 (s, 6H), 1.45-1.91 (m, 2H), 1.01-1.44 (m, 6H), 0.83-1.01 (m, 3H) δ 7.01-7.40 (m, 5H), 3.00-3.28 (m, 3H), 2.45-2.65 (m, 1H), 1.52 (s, 6H), 1.45-1.91 (m, 2H), 1.01-1.44 (m, 6H), 0.83-1.01 (m, 3H) 3-45 (i) P-1 δ 7.85-7.95 (m, 2H), 7.35-7.45 (m, 2H), 7.1-7.3 (m, 5H), 3.94 (br, 1H), 3.2-3.3 (m, 1H), 3.05-3.15 (m, 1H), 1.85-2.0 (m, 2H), 1.57 (s, 3H), 1.55 (s, 3H), 1.33 (s, 9H), 0.95-1.19 (m, 8h), 0.74-0.82 (m, 3H) 3-46 (i) P-2 δ 7.05-7.2 (m, 1H), 6.95-7.05 (m, 1H), 6.85-6.95 (m, 2H), 4.64 (s, 1H), 2.92-3.13 (m, 2H), 2.73-2.89 (m, 1H), 2.30 (s, 3H), 1.46-1.61 (m, 6H), 1.06-1.19 (m, 6H) 3-47 (i) P-2 7.06-7.29 (m, 5H), 4.64 (s, 1H), 3.12 (d, J = 13.4 Hz, 1H), 3.03 (d, J = 13.4 Hz, 1H), 2.73-2.88 (m, 1H), 1.53 (s, 3H), 1.52 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 7.2 Hz, 3H) 3-48 (i) mixture of P-1 and P-2 5:5 δ 6.89-7.47 (m, 8H), 6.13 (br, 1H), 3.20 (s, 2H), 3.12-3.19 (m, 1H), 2.49-2.65 (m, 4H), 1.63 (s, 6H), 1.45-1.62 (m, 4H), 1.20-1.43 (m, 12H), 0.96-1.19 (m, 6H), 0.81-0.93 (m, 6H) δ 6.89-7.47 (m, 8H), 4.11 (s, 1H), 3.11 (s, 2H), 2.49-2.65 (m, 4H), 2.35-2.50 (m, 1H), 1.54 (s, 6H), 1.45-1.62 (m, 4H), 1.20-1.43 (m, 12H), 0.96-1.19 (m, 6H), 0.81-0.93 (m, 6H) 3-49 (i) P-1 δ 7.13-7.19 (m, 3H), 6.73-6.82 (m, 2H), 5.95 (s, 1H), 3.07 (s, 2H), 2.87 (sep, J = 6.9 Hz, 1H), 2.15 (s, 3H), 1.58 (s, 6H), 1.21 (d, J = 7.2 Hz, 6H) 4-01 (i) P-2 δ 7.18-7.34 (m, 5H), 3.75 (s, 3H), 3.48 (s, 2H), 3.41 (s, 2H), 1.87 (s, 6H) 4-03 (i) P-1 δ 7.08-7.30 (m, 7H), 6.87-6.76 (m, 2H), 3.25 (s, 3H), 3.11 (s, 2H), 2.95 (sep, J = 6.9 Hz, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.63 (s, 6H), 1.51-1.70 (m, 2H), 1.21-1.42 (m, 6H), 1.15 (d, J = 6.8 Hz, 6H), 0.89 (t, J = 6.8 Hz, 3H) 4-12 (ii) mixture of P-1 and P-3 8:2 δ 9.26 (s, 1H), 7.1-7.3 (m, 3H), 6.89 (d, J = 6.9 Hz, 2H), 2.82 (sep, J = 6.9 Hz, 1H), 2.20 (t, J = 7.8 Hz, 2H), 1.82 (s, 6H), 1.37 (m, 2H), 1.19 (d, J = 7.3 Hz, 6H), 0.8-0.9 (m, 3H) δ 9.23 (s, 1H), 7.1-7.3 (m, 3H), 7.04 (d, J = 7.0 Hz, 2H), 2.8-3.0 (m, 1H), 2.0-2.15 (m, 2H), 1.79 (s, 6H), 1.37 (m, 2H), 1.21 (d, J = 6.9 Hz, 6H), 0.8-0.9 (m, 3H) 4-13 (ii) P-1 δ 9.87 (s, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.1-7.5 (m, 10H), 2.5-2.6 (m, 2H), 1.97 (s, 6H), 1.5-1.6 (m, 2H), 1.2-1.4 (m, 6H), 0.7-0.9 (m, 3H) 4-14 (ii) mixture of P-1 and P-2 6:4 δ 9.68 (s, 1H), 7.0-8.0 (m, 14H), 2.4-2.6 (m, 2H), 1.92 (s, 6H), 1.0-1.5 (m, 8H), 0.7-0.9 (m, 3H) δ 7.0-8.0 (m, 14H), 3.31 (s, 1H), 2.4-2.6 (m, 2H), 1.87 (s, 6H), 1.0-1.5 (m, 8H), 0.7-0.9 (m, 3H) 4-15 (ii) P-1 δ 9.78 (s, 1H), 7.05-7.35 (m, 13H), 2.5-2.6 (m, 2H), 1.95 (s, 6H), 1.5-1.6 (m, 2H), 1.28 (s, 9H), 1.2-1.4 (m, 6H), 0.7-0.9 (m, 3H) 4-16 (ii) P-1 δ 9.59 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.1-7.35 (m, 3H), 7.00 (d, J = 7.0 Hz, 2H), 2.4-2.5 (m, 2H), 1.90 (s, 6H), 1.8-1.9 (m, 2H), 1.05-1.45 (m, 6H), 1.31 (s, 9H), 0.7-0.9 (m, 3H) 4-17 (ii) mixture of P-1 and P-3 1:6 δ 9.63 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.35-7.45 (m, 4H), 7.41 (d, J = 8.6 Hz, 2H), 2.4-2.5 (m, 2H), 1.88 (s, 6H), 1.8-1.9 (m, 2H), 1.0-1.4 (m, 6H), 1.30 (s, 9H), 0.7-0.8 (m, 3H) δ 9.7-9.8 (m, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.1-7.6 (m, 6H), 2.4-2.5 (m, 2H), 1.88 (s, 6H), 1.8-1.9 (m, 2H), 1.0-1.4 (m, 6H), 1.30 (s, 9H), 0.7-0.8 (m, 3H) 4-18 (ii) mixture of P-1 and P-3 8:2 δ 9.96 (s, 1H), 7.3-7.7 (m, 9H), 7.19 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 3.20 (s, 2H), 2.45-2.6 (m, 2H), 1.56 (s, 6H), 1.35-1.55 (m, 2H), 1.2-1.35 (m, 6H), 0.8-0.9 (m, 3H) δ 9.45 (br, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.1-7.7 (m, 11H), 3.26 (s, 2H), 2.45-2.6 (m, 2H), 1.50 (s, 6H), 1.35-1.55 (m, 2H), 1.2-1.35 (m, 6H), 0.8-0.9 (m, 3H) 4-19 (ii) mixture of P-1 and P-3 8:2 δ 9.87 (s, 1H), 6.8-7.9 (m, 8H), 3.17 (s, 2H), 2.4-2.55 (m, 2H), 1.53 (s, 6H), 1.28 (s, 9H), 1.0-1.5 (m, 8H), 0.7-0.9 (m, 3H) δ 9.3-9.4 (m, 1H), 6.8-7.9 (m, 8H), 3.23 (s, 2H), 2.2-2.4 (m, 2H), 1.47 (s, 6H), 1.25 (s, 9H), 1.0-1.5 (m, 8H), 0.7-0.9 (m, 3H) 4-20 (ii) mixture of P-1 and P-3 6:4 δ 9.90 (s, 1H), 7.3-7.7 (m, 9H), 6.80 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.3 Hz, 2H), 3.67 (s, 3H), 3.13 (s, 2H), 2.4-2.6 (m, 2H), 1.54 (s, 6H), 1.4-1.6 (m, 2H), 1.0-1.2 (m, 6H), 0.7-0.9 (m, 3H) δ 9.4-9.5 (m, 1H), 6.6-7.8 (m, 13H), 3.68 (s, 3H), 3.17 (s, 2H), 2.4-2.6 (m, 2H), 1.48 (s, 6H), 1.28 (s, 9H), 1.4-1.6 (m, 2H), 1.0-1.2 (m, 6H), 0.7-0.9 (m, 3H) 4-21 (ii) mixture of P-1 and P-3 7:3 δ 9.80 (s, 1H), 6.6-7.9 (m, 8H), 3.67 (s, 3H), 3.11 (s, 2H), 2.4-2.6 (m, 2H), 1.51 (s, 6H), 1.28 (s, 9H), 1.0-1.6 (m, 8H), 0.7-0.9 (m, 3H) δ 9.35 (m, 1H), 6.6-7.9 (m, 8H), 3.68 (s, 3H), 3.15 (s, 2H), 2.2-2.4 (m, 2H), 1.45 (s, 6H), 1.0-1.6 (m, 8H), 1.25 (s, 9H), 0.7-0.9 (m, 3H) 4-22 (ii) mixture of P-1 and P-3 6:4 δ 9.43 (s, 1H), 6.66 (s, 4H), 3.67 (s, 3H), 3.01 (s, 2H), 2.6-2.8 (m, 2H), 2.2-2.3 (m, 2H), 1.44 (s, 6H), 1.3-1.5 (m, 2H), 1.07 (d, J = 6.8 Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H) δ 8.78 (s, 1H), 6.91 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.3 Hz, 2H), 3.68 (s, 3H), 3.08 (s, 2H), 2.7-2.9 (m, 2H), 2.0-2.2 (m, 2H), 1.39 (s, 6H), 1.3-1.5 (m, 2H), 1.07 (d, J = 6.8 Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H) 4-23 (i) mixture of P-1 and P-2 9:1 δ 8.0-8.1 (m, 2H), 7.6-7.7 (m, 2H), 7.15-7.3 (m, 3H), 7.05-7.15 (m, 2H), 6.37 (br, 1H), 3.92 (s, 3H), 3.27 (s, 2H), 3.12-3.19 (m, 1H), 1.65 (s, 6H), 1.08 (d, J = 7.2 Hz, 6H) δ 8.0-8.1 (m, 2H), 7.6-7.7 (m, 2H), 7.15-7.3 (m, 3H), 7.05-7.15 (m, 2H), 4.2-4.3 (m, 1H), 3.92 (s, 3H), 3.1-3.2 (m, 2H), 2.35-2.5 (m, 1H), 1.65 (s, 6H), 0.95-1.05 (m, 6H) 4-27 (i) P-1 δ 9.71 (s, 1H), 7.13-7.33 (m, 3H)., 7.05-7.12 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.23 (sep, J = 6.9 Hz, 1H), 1.94 (s, 6H), 1.36 (t, 7.3 Hz, 3H), 1.30 (d, J = 6.8 Hz, 6H) 4-28 (ii) mixture of P-1 and P-3 6:4 δ 9.66 (s, 1H), 6.9-8.3 (m, 11H), 3.60 (s, 2H), 2.82 (sep, J = 6.7 Hz, 1H), 2.58 (t, J = 8.0 Hz, 2H), 1.60 (s, 6H), 1.5-1.7 (m, 2H), 1.2-1.4 (m, 6H), 0.97 (d, J = 5.9 Hz, 6H), 0.87 (t, J = 7.0 Hz, 3H) 9.29 (s, 1H), 6.9-8.3 (m, 11H), 3.69 (s, 2H), 2.95 (sep, J = 6.6 Hz, 1H), 2.58 (t, J = 8.0 Hz, 2H), 1.57 (s, 6H), 1.5-1.7 (m, 2H), 1.2-1.4 (m, 6H), 0.99 (d, J = 6.3 Hz, 6H), 0.87 (t, J = 7.0 Hz, 3H) 4-29 (ii) mixture of P-1 and P-3 7:3 δ 9.66 (s, 1H), 6.9-8.3 (m, 11H), 3.60 (s, 2H), 2.82 (sep, J = 6.5 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 1.59 (s, 6H), 1.5-1.7 (m, 2H), 1.2-1.4 (m, 10H), 0.97 (d, J = 6.6 Hz, 6H), 0.86 (t, J = 6.4 Hz, 3H) δ 9.29 (s, 1H), 6.9-8.3 (m, 11H), 3.69 (s, 2H), 2.85-3.0 (m, 1H), 2.58 (t, J = 7.7 Hz, 2H), 1.59 (s, 6H), 1.5-1.7 (m, 2H), 1.2-1.4 (m, 10H), 0.97 (d, J = 6.6 Hz, 6H), 0.86 (t, J = 6.4 Hz, 3H) 4-30 (ii) mixture of P-1 and P-3 7:3 δ 9.68 (s, 1H), 6.8-8.3 (m, 11H), 3.59 (s, 2H), 2.82 (sep, J = 6.7 Hz, 1H), 1.65-1.8 (m, 5H), 1.59 (s, 6H), 1.1-1.5 (m, 6H), 0.98 (d, J = 6.6 Hz, 6H) δ 9.29 (s, 1H), 6.8-8.3 (m, 11H), 3.69 (s, 2H), 2.85-3.0 (m, 1H), 1.65-1.8 (m, 5H), 1.59 (s, 6H), 1.1-1.5 (m, 6H), 1.04 (d, J = 6.6 Hz, 6H) 4-31 (ii) mixture of P-1 and P-3 7:3 δ 10.17 (s, 1H), 6.3-8.3 (m, 10H), 3.62 (s, 2H), 2.95 (sep, J = 5.2 Hz, 1H), 1.57 (s, 6H), 1.03 (d, J = 5.3 Hz, 6H) δ 9.69 (s, 1H), 6.3-8.3 (m, 10H), 3.71 (s, 2H), 3.24 (sep, J = 5.2 Hz, 1H), 1.54 (s, 6H), 1.09 (d, J = 5.3 Hz, 6H) 4-32 (ii) mixture of P-1 and P-3 5:5 δ 9.81 (s, 1H), 8.0-8.15 (m, 1H), 7.7-7.85 (m, 2H), 6.9-7.6 (m, 8H), 3.62 (s, 2H), 2.58 (t, J = 7.9 Hz, 2H), 2.3-2.45 (m, 2H), 1.57 (s, 6H), 1.0-1.4 (m, 16H), 0.85-1.0 (m, 3H), 0.7-0.85 (m, 3H) δ 9.72 (s, 1H), 8.25-8.35 (m, 1H), 7.85-7.95 (m, 2H), 6.9-7.6 (m, 8H), 3.72 (s, 2H), 2.58 (t, J = 7.9 Hz, 2H), 2.3-2.45 (m, 2H), 1.54 (s, 6H), 1.0-1.4 (m, 16H), 0.85-1.0 (m, 3H), 0.7-0.85 (m, 3H) 4-33 (ii) mixture of P-1 and P-3 8:2 δ 9.61 (s, 1H), 6.8-8.3 (m, 11H), 3.59 (s, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.4-2.55 (m, 1H), 1.59 (s, 6H), 1.0-1.7 (m, 18H), 0.8-0.9 (m, 3H) δ 9.28 (s, 1H), 6.8-8.3 (m, 11H), 3.69 (s, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.4-2.55 (m, 1H), 1.59 (s, 6H), 1.0-1.7 (m, 18H), 0.8-0.9 (m, 3H) 4-34 (ii) P-1 δ 10.25 (s, 1H), 8.1-8.2 (m, 1H), 7.8-7.9 (m, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.45-7.55 (m, 3H), 7.35 (t J = 8.1 Hz, 1H), 7.15-7.25 (m, 4H), 7.07 (d, J = 7.1 Hz, 1H), 6.3-6.4 (m, 1H), 5.95-6.05 (m, 1H), 3.71 (s, 2H), 2.59 (t, J = 7.8 Hz, 2H), 1.63 (s, 6H), 1.45-1.7 (m, 2H), 1.2-1.45 (m, 6H), 0.8-0.9 (m, 3H) 4-35 (ii) mixture of P-1 and P-3 8:2 δ 9.74 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.7 (m, 1H), 3.42 (s, 2H), 2.89 (sep, J = 6.5 Hz, 1H), 2.57 (t, J = 7.7 Hz, 2H), 1.57 (s, 6H), 1.45-1.65 (m, 2H), 1.2-1.4 (m, 6H), 1.06 (d, J = 6.5 Hz, 6H), 0.8-0.9 (m, 3H) δ 9.41 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.7-6.8 (m, 1H), 3.48 (s, 2H), 2.95-3.1 (m, 1H), 2.57 (t, J = 7.7 Hz, 2H), 1.57 (s, 6H), 1.45-1.65 (m, 2H), 1.2-1.4 (m, 6H), 1.06 (d, J = 6.5 Hz, 6H), 0.8-0.9 (m, 3H) 4-36 (ii) mixture of P-1 and P-3 8:2 δ 9.74 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.7 (m, 1H), 3.43 (s, 2H), 2.8-2.95 (m, 1H), 2.57 (t, J = 7.7 Hz, 2H), 1.52 (s, 6H), 1.5-1.65 (m, 2H), 1.2-1.4 (m, 10H), 1.06 (d, J = 6.2 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H) δ 9.45-9.55 (m, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.7-6.8 (m, 1H), 3.47 (s, 2H), 2.95-3.1 (m, 1H), 2.57 (t, J = 7.7 Hz, 2H), 1.52 (s, 6H), 1.5-1.65 (m, 2H), 1.2-1.4 (m, 10H), 1.06 (d, J = 6.2 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H) 4-37 (ii) mixture of P-1 and P-3 7:3 δ 9.76 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.8 (m, 1H), 3.42 (s, 2H), 2.89 (sep, J = 6.5 Hz, 1H), 2.4-2.55 (m, 1H), 1.65-1.9 (m, 5H), 1.52 (s, 6H), 1.1-1.5 (m, 5H), 1.07 (d, J = 6.6 Hz, 6H) δ 9.41 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.8 (m, 1H), 3.4-3.5 (m, 2H), 2.95-3.1 (m, 1H), 2.4-2.55 (m, 1H), 1.65-1.9 (m, 5H), 1.52 (s, 6H), 1.1-1.5 (m, 5H), 1.07 (d, J = 6.6 Hz, 6H) 4-38 (ii) mixture of P-1 and P-3 7:3 δ 10.15 (s, 1H), 7.61 (s, 1H), 7.26 (d, J = 3.8 Hz, 1H), 6.6-6.95 (m, 2H), 6.50 (s, 1H), 6.32 (d, J = 5.4 Hz, 1H), 3.42 (s, 2H), 3.02 (sep, J = 5.2 Hz, 1H), 1.52 (s, 6H), 1.12 (d, J = 5.2 Hz, 6H) δ 9.82 (s, 1H), 7.59 (s, 1H), 7.29 (d, J = 3.7 Hz, 1H), 6.6-6.95 (m, 2H), 6.50 (s, 1H), 6.32 (d, J = 5.4 Hz, 1H), 3.50 (s, 2H), 3.02 (sep, J = 5.2 Hz, 1H), 1.50 (s, 6H), 1.19 (d, J = 5.3 Hz, 6H) 4-39 (ii) P-1 δ 9.84 (s, 1H), 7.1-7.5 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.8 (m, 1H), 3.4-3.6 (m, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.3-2.45 (m, 2H), 1.50 (s, 6H), 1.05-1.65 (m, 16H), 0.75-0.9 (m, 6H) 4-40 (ii) mixture of P-1 and P-3 7:3 δ 9.70 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.8 (m, 1H), 3.42 (s, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.4-2.55 (m, 1H), 1.52 (s, 6H), 1.05-1.75 (m, 18H), 0.8-0.9 (m, 3H) δ 9.34 (s, 1H), 7.1-7.35 (m, 5H), 6.8-6.95 (m, 1H), 6.6-6.8 (m, 1H), 3.48 (s, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.4-2.55 (m, 1H), 1.52 (s, 6H), 1.05-1.75 (m, 18H), 0.8-0.9 (m, 3H) 4-41 (ii) P-1 δ 10.30 (s, 1H), 7.53 (s, 1H), 7.28 (d, J = 5.2 Hz, 1H), 7.20 (s, 4H), 6.90 (t, J = 3.5 Hz, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 6.07 (s, 1H), 3.50 (s, 2H), 2.59 (t, J = 7.5 Hz, 2H), 1.58 (s, 6H), 1.5-1.65 (m, 2H), 1.2-1.4 (m, 6H), 0.8-0.9 (m, 3H) 4-42 (ii) mixture of P-1 and P-3 9:1 δ 9.57 (s, 1H), 7.1-7.25 (m, 4H), 2.87 (sep, J = 7.1 Hz, 1H), 2.56 (t, J = 8.0 Hz, 2H), 1.62 (s, 6H), 1.45-1.85 (m, 13H), 1.25-1.4 (m, 12H), 1.10 (d, J = 6.8 Hz, 6H), 0.8-0.9 (m, 3H) δ 9.60 (s, 1H), 7.1-7.25 (m, 4H), 3.0-3.15 (m, 1H), 2.56 (t, J = 8.0 Hz, 2H), 1.62 (s, 6H), 1.45-1.85 (m, 13H), 1.25-1.4 (m, 12H), 1.21 (d, J = 7.1 Hz, 6H), 0.8-0.9 (m, 3H) 4-43 (ii) P-1 δ 9.57 (s, 1H), 7.17 (s, 4H), 2.8-2.95 (m, 1H), 2.56 (t, J = 7.8 Hz, 2H), 1.62 (s, 6H), 1.2-1.9 (m, 29H), 1.10 (d, J = 6.7 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H) 4-44 (ii) P-1 δ 9.58 (s, 1H), 7.19 (dd, J = 8.2 Hz, 13.4 Hz, 4H), 2.8-2.95 (m, 1H), 2.4-2.55 (m, 1H), 1.61 (s, 6H), 1.15-1.9 (m, 27H), 1.11 (d, J = 6.8 Hz, 6H) 4-45 (ii) mixture of P-1 and P-3 8:2 δ 9.94 (s, 1H), 7.58 (s, 1H), 6.4-6.5 (m, 1H), 6.27 (d, J = 2.4 Hz, 1H), 3.02 (sep, J = 5.2 Hz, 1H), 1.64 (s, 6H), 1.3-1.85 (m, 17H), 1.13 (d, J = 5.1 Hz, 6H) δ 9.94 (s, 1H), 7.56 (s, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.4-6.5 (m, 1H), 3.35-3.45 (m, 1H), 1.64 (s, 6H), 1.3-1.85 (m, 17H), 1.26 (d, J = 5.3 Hz, 6H) 4-46 (ii) P-1 δ 9.64 (s, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 2.45-2.65 (m, 4H), 1.59 (s, 6H), 1.05-1.85 (m, 33H), 0.7-0.9 (m, 6H) 4-47 (ii) P-1 δ 9.53 (s, 1H), 7.1-7.2 (m, 4H), 2.56 (t, J = 8.0 Hz, 2H), 2.45-2.55 (m, 1H), 1.61 (s, 6H), 1.1-1.8 (m, 35H), 0.86 (t, J = 6.8 Hz, 3H) 4-48 (ii) P-1 δ 10.04 (s, 1H), 7.56 (s, 1H), 7.17 (s, 4H), 6.40 (s, 1H), 6.09 (d, J = 2.9 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 1.75-1.9 (m, 6H), 1.65 (s, 6H), 1.2-1.7 (m, 19H), 0.8-0.95 (m, 3H) 4-49 (ii) mixture of P-1 and P-3 6:4 δ 10.21 (s, 1H), 7.2-7.4 (m, 7H), 7.05 (d, J = 4.9 Hz, 2H), 2.93 (s, 2H), 2.8-2.9 (m, 1H), 2.5-2.6 (m, 2H), 1.5-1.65 (m, 2H), 0.9-1.35 (m, 16H), 0.86 (t, J = 5.3 Hz, 3H) δ 9.73 (s, 1H), 7.2-7.4 (m, 7H), 6.96 (d, J = 4.6 Hz, 2H), 2.99 (s, 2H), 2.9-3.05 (m, 1H), 2.5-2.6 (m, 2H), 1.5-1.65 (m, 2H), 0.9-1.35 (m, 16H), 0.86 (t, J = 5.3 Hz, 3H) 4-50 (ii) mixture of P-1 and P-3 6:4 δ 10.21 (s, 1H), 7.1-7.3 (m, 7H), 7.05 (d, J = 4.8 Hz, 2H), 2.93 (s, 2H), 2.8-2.9 (m, 1H), 2.5-2.6 (m, 2H), 1.5-1.6 (m, 2H), 0.9-1.35 (m, 20H), 0.86 (t, J = 5.4 Hz, 3H) δ 9.72 (s, 1H), 7.1-7.3 (m, 7H), 6.95 (d, J = 4.3 Hz, 2H), 2.99 (s, 2H), 2.9-3.0 (m, 1H), 2.5-2.6 (m, 2H), 1.5-1.6 (m, 2H), 0.9-1.35 (m, 20H), 0.86 (t, J = 5.4 Hz, 3H) 4-51 (ii) mixture of P-1 and P-3 6:4 δ 10.21 (s, 1H), 7.1-7.3 (m, 7H), 7.05 (d, J = 4.6 Hz, 2H), 2.93 (s, 2H), 2.8-2.9 (m, 1H), 2.4-2.6 (m, 1H), 1.75-1.85 (m, 4H), 0.95-1.5 (m, 16H) δ 9.74 (s, 1H), 7.1-7.3 (m, 7H), 6.9-7.0 (m, 2H), 2.98 (s, 2H), 2.9-3.0 (m, 1H), 2.4-2.6 (m, 1H), 1.65-1.75 (m, 4H), 0.95-1.5 (m, 16H) 4-52 (ii) mixture of P-1 and P-3 6:4 δ 10.57 (s, 1H), 7.53 (s, 1H), 7.1-7.25 (m, 5H), 7.04 (d, J = 4.6 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.45-6.5 (m, 1H), 2.92 (s, 2H), 2.9-3.05 (m, 1H), 1.0-1.25 (m, 8H), 0.85-1.0 (m, 2H) δ 10.21 (s, 1H), 7.59 (s, 1H), 7.1-7.25 (m, 5H), 6.97 (d, J = 4.5 Hz, 1H), 6.4-6.5 (m, 1H), 6.28 (d, J = 2.4 Hz, 1H), 2.98 (s, 2H), 2.75-2.85 (m, 1H), 1.0-1.25 (m, 8H), 0.85-1.0 (m, 2H) 4-53 (ii) mixture of P-1 and P-3 7:3 δ 10.41 (s, 1H), 6.95-7.45 (m, 9H), 2.95-3.1 (m, 2H), 2.55 (t, J = 5.8 Hz, 2H), 2.40 (d, J = 5.8 Hz, 2H), 1.5-1.65 (m, 2H), 1.0-1.4 (m, 16H), 0.75-0.95 (m, 8H) δ 9.80 (s, 1H), 6.95-7.45 (m, 9H), 2.95-3.1 (m, 2H), 2.55 (t, J = 5.8 Hz, 2H), 2.40 (d, J = 5.8 Hz, 2H), 1.5-1.65 (m, 2H), 1.0-1.4 (m, 16H), 0.75-0.95 (m, 8H) 4-54 (ii) mixture of P-1 and P-3 6:4 δ 10.22 (s, 1H), 7.1-7.3 (m, 7H), 7.0-7.1 (m, 2H), 2.92 (s, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.45-2.7 (m, 1H), 1.5-1.65 (m, 8H), 1.25-1.5 (m, 8H), 1.0-1.25 (m, 4H), 0.8-0.95 (m, 5H)) δ 9.69 (s, 1H), 7.1-7.3 (m, 7H), 6.9-7.0 (m, 2H), 2.98 (s, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.45-2.7 (m, 1H), 1.5-1.65 (m, 8H), 1.25-1.5 (m, 8H), 1.0-1.25 (m, 4H), 0.8-0.95 (m, 5H)) 4-55 (ii) P-1 δ 10.21 (s, 1H), 7.53 (s, 1H), 7.05-7.35 (m, 9H), 6.40 (s, 1H), 6.08 (s, 1H), 3.10 (s, 2H), 2.57 (t, J = 5.8 Hz, 2H), 1.5-1.65 (m, 2H), 1.2-1.4 (m, 6H), 0.9-1.0 (m, 2H), 0.8-0.9 (m, 5H) 4-56 (ii) mixture of P-1 and P-3 7:3 δ 9.68 (s, 1H), 7.1-7.35 (m, 4H), 6.85-7.1 (m, 2H), 6.65-6.85 (m, 2H), 3.09 (s, 2H), 2.86 (sep, J = 6.8 Hz, 1H), 2.57 (t, J = 7.4 Hz, 2H), 2.22 (s, 3H), 1.50 (s, 6H), 1.4-1.65 (m, 2H), 1.15-1.4 (m, 10H), 1.02 (d, J = 6.2 Hz, 6H), 0.8-0.95 (m, 3H) δ 9.29 (s, 1H), 7.1-7.35 (m, 4H), 6.85-7.1 (m, 4H), 3.14 (s, 2H), 2.95-3.05 (m, 1H), 2.57 (t, J = 7.4 Hz, 2H), 2.22 (s, 3H), 1.50 (s, 6H), 1.4-1.65 (m, 2H), 1.15-1.4 (m, 10H), 1.0-1.1 (m, 6H), 0.8-0.95 (m, 3H) 4-57 (ii) mixture of P-1 and P-3 7:3 δ 9.69 (s, 1H), 7.15-7.2 (m, 4H), 6.85-7.0 (m, 2H), 6.73 (d, J = 7.9 Hz, 2H), 3.09 (s, 2H), 2.85 (sep, J = 6.7 Hz, 1H), 2.45-2.55 (m, 1H), 2.22 (s, 3H), 1.65-1.9 (m, 5H), 1.50 (s, 6H), 1.15-1.5 (m, 5H), 1.02 (d, J = 6.8 Hz, 6H) δ 9.29 (s, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.15-7.2 (m, 2H), 6.85-7.0 (m, 4H), 3.14 (s, 2H), 2.95-3.05 (m, 1H), 2.45-2.55 (m, 1H), 2.22 (s, 3H), 1.65-1.9 (m, 5H), 1.50 (s, 6H), 1.15-1.5 (m, 5H), 1.06 (d, J = 7.1 Hz, 6H) 4-58 (ii) mixture of P-1 and P-3 7:3 δ 10.11 (s, 1H), 7.61 (s, 1H), 6.96 (d, J = 5.6 Hz, 2H), 6.74 (d, J = 5.7 Hz, 2H), 6.50 (s, 1H), 6.32 (s, 1H), 3.10 (s, 2H), 2.98 (sep, J = 5.3 Hz, 1H), 2.22 (s, 3H), 1.49 (s, 6H), 1.07 (d, J = 5.2 Hz, 6H) δ 9.70 (s, 1H), 7.59 (s, 1H), 6.85-7.05 (m, 4H), 6.50 (s, 1H), 6.32 (s, 1H), 3.17 (s, 2H), 2.98 (sep, J = 5.3 Hz, 1H), 2.22 (s, 3H), 1.46 (s, 6H), 1.15 (d, J = 4.6 Hz, 6H) 4-59 (ii) mixture of P-1 and P-3 5:5 δ 9.79 (s, 1H), 7.1-7.3 (m, 4H), 6.9-7.05 (m, 2H), 6.77 (d, J = 7.7 Hz, 2H), 3.18 (s, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.35-2.5 (m, 2H), 2.22 (s, 3H), 1.49 (s, 6H), 1.55-1.65 (m, 2H), 1.2-1.45 (m, 8H), 1.05-1.2 (m, 6H), 0.85-0.9 (m, 3H), 0.7-0.85 (m, 3H) δ 9.71 (s, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.1-7.3 (m, 4H), 6.9-7.05 (m, 2H), 3.11 (s, 2H), 2.57 (t, J = 7.5 Hz, 2H), 2.35-2.5 (m, 2H), 2.22 (s, 3H), 1.46 (s, 6H), 1.55-1.65 (m, 2H), 1.2-1.45 (m, 8H), 1.05-1.2 (m, 6H), 0.85-0.9 (m, 3H), 0.7-0.85 (m, 3H) 4-60 (ii) mixture of P-1 and P-3 7:3 δ 9.64 (s, 1H), 7.15-7.25 (m, 4H), 6.85-7.05 (m, 2H), 6.65-6.8 (m, 2H), 3.09 (s, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2.4-2.65 (m, 1H), 2.22 (s, 3H), 1.45-1.75 (m, 8H), 1.50 (s, 6H), 1.25-1.4 (m, 8H), 1.05-1.25 (m, 2H), 0.8-0.95 (m, 3H) δ 9.2-9.3 (m, 1H), 7.15-7.35 (m, 4H), 6.85-7.05 (m, 4H), 3.1-3.2 (m, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2.4-2.65 (m, 1H), 2.22 (s, 3H), 1.45-1.75 (m, 8H), 1.50 (s, 6H), 1.25-1.4 (m, 8H), 1.05-1.25 (m, 2H), 0.8-0.95 (m, 3H) 4-61 (ii) P-1 δ 10.23 (s, 1H), 7.52 (s, 1H), 7.20 (s, 4H), 7.00 (d, J = 7.4 Hz, 2H), 6.86 (d, J = 7.8 Hz, 2H), 6.37 (d, J = 1.6 Hz, 1H), 6.03 (d, J = 2.82 Hz, 1H), 3.19 (s, 2H), 2.59 (t, J = 7.8 Hz, 2H), 2.22 (s, 3H), 1.54 (s, 6H), 1.45-1.7 (m, 2H), 1.2-1.45 (m, 6H), 0.8-0.9 (m, 3H) 4-62 (ii) P-1 δ 7.22 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 7.7 Hz, 2H), 6.69 (d, J = 7.9 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.01 (s, 2H), 2.9-3.0 (m, 1H), 2.58 (t, J = 7.8 Hz, 2H), 2.23 (s, 3H), 1.45-1.65 (m, 2H), 1.51 (s, 6H), 1.2-1.4 (m, 6H), 1.09 (d, J = 6.9 Hz, 6H), 1.07 (t, J = 7.1 Hz, 3H). 0.8-0.9 (m, 3H) 4-71 (i) P-1 δ 7.15-7.63 (m, 8H), 6.90-6.98 (m, 2H), 3.17 (s, 2H), 2.60-2.74 (m, 1H), 1.64 (s, 6H), 0.96 (d, J = 6.9 Hz, 6H) 4-72 m.p. 117~119° C. 4-73 m.p. 69~71° C. 4-74 m.p. 113~115° C. 4-75 m.p. 102~104° C. 4-76 m.p. 101~103° C. 4-80 m.p. 88~90° C. 4-81 m.p. 58~60° C. 4-82 m.p. 133~135° C. 4-83 m.p. 109~111° C. 4-84 m.p. 108~110° C. 4-85 m.p. 88~90° C. 4-86 m.p. 140~142° C. 4-87 m.p. 108~110° C. 4-88 (i) P-1 δ 12.7-13.1 (br, 1H), 7.12-7.21 (m, 3H), 6.84-6.94 (m, 2H), 3.11 (s, 2H), 3.04-3.15 (m, 1H), 2.42 (s, 3H), 1.58 (s, 6H), 1.27 (d, J = 6.9 Hz, 6H) 4-89 (i) P-1 δ 10.7-11.4 (br, 1H), 7.12-7.22 (m, 3H), 6.84-6.95 (m, 2H), 3.87 (s, 3H), 3.16 (s, 2H), 2.98-3.12 (m, 1H), 2.25 (s, 3H), 1.57 (s, 6H),. 1.21 (d, J = 6.8 Hz, 6H) 4-90 m.p. 149~151° C. 4-91 (ii) P-1 δ 9.6-9.9 (br, 1H), 7.1-7.25 (m, 3H), 6.8-6.9 (m, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.11 (s, 2H), 3.07 (sep, J = 7.5 Hz, 1H), 2.11 (s, 3H), 1.5-1.7 (m, 2H), 1.49 (s, 6H), 1.2-1.4 (m, 6H), 1.09 (d, J = 6.8 Hz, 6H), 0.87 (t, J = 6.8 Hz, 3H)

Formulation Example 1

A granule preparation containing the following ingredients is prepared.

Ingredients Compound represented by the formula (I)  10 mg Lactose 700 mg Corn Starch 274 mg HPC-L  16 mg Total 1000 mg 

A compound represented by the formula (1) and lactose are sifted through a 60-mesh sieve. Corn starch is sifted through a 120-mesh sieve. They are mixed in a V-type blender. The powder mixture is kneaded with a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution, granulated (extrusion granulation, die size 0.5-1 mm) and dried. The resulting dry granules are sifted through a shaking sieve (12/60 mesh) to obtain a granule preparation.

Formulation Example 2

A powder preparation for capsulation containing the following ingredients is prepared.

Ingredients Compound represented by the formula (I) 10 mg Lactose 79 mg Corn Starch 10 mg Magnesium Stearate  1 mg Total 100 mg 

A compound represented by the formula (1) and lactose are sifted through a 60-mesh sieve. Corn starch is sifted through a 120-mesh sieve. They are mixed with magnesium stearate in a V-type blender. The 10% powder is put in hard gelatin capsules No. 5, 100 mg each.

Formulation Example 3

A granule preparation for capsulation containing the following ingredients is prepared.

Ingredients Compound represented by the formula (I) 15 mg Lactose 90 mg Corn Starch 42 mg HPC-L  3 mg Total 150 mg 

A compound represented by the formula (1) and lactose are sifted through a 60-mesh sieve. Corn starch is sifted through a 120-mesh sieve. They are mixed in a V-type blender. The powder mixture is kneaded with a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution, granulated and dried. The resulting dry granules are sifted through a shaking sieve (12/60 mesh). The granules are put in hard capsules No. 4, 150 mg each.

Formulation Example 4

A tablet preparation containing the following ingredients is prepared.

Ingredients Compound represented by the formula (I) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg Magnesium Stearate  5 mg CMC-Na 15 mg Total 150 mg 

A compound represented by the formula (1), lactose, microcrystalline cellulose and CMC—Na (carboxymethylcellulose sodium salt) are sifted through a 60-mesh sieve and mixed. The powder mixture is mixed with magnesium stearate to give a bulk powder mixture. The powder mixture is compressed directly into 150 mg tablets.

Formulation Example 5

An intravenous preparation is prepared as follows.

Compound represented by the formula (I)  100 mg Saturated Fatty Acid Glyceride 1000 mL

Solutions having the above-mentioned composition are usually administered to a patient intravenously at a rate of 1 mL per 1 minute.

Assay Example

Next, usefulness of compounds of the present invention as inhibitors of myeloma cell growth will be demonstrated specifically with reference to the following assay example, but the present invention is by no means restricted thereto. The CO₂ concentration (%) in a CO₂ incubator is expressed by the ratio of CO₂ in the atmosphere in vol %.

Aassay Example Cell Proliferation Assay

Myeloma cell strain RPMI8226 (DS Pharma Biomedical Co., Ltd.) was incubated in liquid culture in a CO₂ incubator (5% CO₂) in RPMI1640 medium containing 10% (v/v) fetal calf serum. The resulting cells were suspended in RPMI640 medium(GIBCO) containing 10% (v/v) fetal calf serum and plated in 96-well flat-bottomed microplates (Corning Incorporated) in 100 μl/mL (400000 cells/well) per well. Furtheremore, each of the compounds prepared in Synthetic Examples was dissolved in dimethylsulfoxide and added at 0.1% (v/v) to final concentrations of 0.1 to 10 μg/mL. As the negative control, dimethyl sulfoxide was added at 0.1% (v/v).

After 4 days of incubation at 37° C. in liquid culture in a CO₂ incubator (5% CO₂), the viable cells were counted by the WST assay. A 10-μl aliquot of Cell Counting Kit-8 reagent solution (Dojindo Molecular Technologies, Inc.) was added to each well and incubated in a CO₂ incubator (5% CO₂) for 4 hours for color reaction, and light absorbance was measured at 450 nm by using a microplate reader. As the cell growth inhibitory activities in the presence of the test compounds relative to that in the absence of them (negative control), the concentrations (IC50) yielding 50% inhibition of cell proliferation were calculated. The results indicate that the compounds of the present invention greatly inhibited growth of RPMI8226 cells and confirm that the compounds of the present invention have growth inhibitory activities on myeloma cells.

The IC50 values (μg/mL) for test compounds against RPMI8226 cells were shown in Table 22.

TABLE 22 IC50 No. (μg/mL) 1-03 4.0 1-07 8.1 3-01 11.1 3-02 11.6 3-03 6.4 3-07 8.8 2-01 10.6 2-03 6.3 2-05 5.3 2-06 10.8 2-07 7.4 2-09 8.9 2-10 8.4 2-12 4.9 2-14 6.6 2-15 5.8 2-16 11.2 2-19 13.4 2-20 38.8 2-21 6.8 2-22 4.2 2-23 0.16 2-24 6.8 2-25 6.2 2-28 68.6 2-29 14.5 2-31 5.7 2-32 4.1 2-33 12.3 2-49 3.6 2-34 6.7 2-35 5.6 2-36 17.7 2-37 3.9 2-39 4.4 2-40 6.5 2-43 7.9 2-44 7.7 2-45 20.7 2-46 3.9 2-47 3.3 2-48 6.4 2-50 3.9 3-05 4.9 3-06 7.7 3-07 5.3 3-09 4.3 3-10 7.6 3-11 4.8 3-12 5.4 3-13 5.4 3-14 7.9 3-16 3.5 3-17 4.4 3-18 7.4 3-19 4.3 3-20 6.6 3-21 4.5 3-22 3.9 3-23 8.5 3-24 4.2 3-25 7.4 3-27 7.7 3-28 4.9 3-29 5.5 3-30 24.9 3-31 6.4 3-32 27.1 3-33 5.9 3-34 3.2 3-35 3.8 3-38 4.2 3-39 0.4 3-40 76.7 3-41 17.0 3-43 8.0 3-44 3.3 3-45 5.6 3-46 3.3 3-47 3.3 3-49 4.3 4-01 11.1 4-03 6.4 4-12 5.6 4-13 8.3 4-14 3.8 4-15 10.2 4-16 4.2 4-17 5.6 4-18 5.6 4-19 21.6 4-20 4.8 4-21 6.1 4-22 4.1 4-23 6.3 4-27 5.5 4-28 19.5 4-30 43.2 4-31 3.3 4-33 54.6 4-34 18.7 4-35 10.5 4-36 13.5 4-37 8.5 4-38 3.4 4-39 10.0 4-40 9.9 4-41 12.5 4-45 3.9 4-48 8.5 4-49 3.4 4-50 3.3 4-51 3.2 4-52 8.4 4-53 4.5 4-54 36.1 4-55 11.7 4-56 30.2 4-57 10.0 4-58 3.3 4-59 22.5 4-60 38.6 4-61 6.4 4-71 3.2 4-72 4.3 4-73 5.9 4-74 6.6 4-75 3.2 4-76 3.6 4-80 9.6 4-81 5.4 4-82 6.7 4-83 7.1 4-84 3.2 4-85 5.4 4-86 3.3 4-87 9.9 4-88 3.7 4-89 4.7 4-90 5.5 4-91 57.7

INDUSTRIAL APPLICABILITY

The pyrazole compounds of the present invention show excellent growth inhibition activity on myeloma cells and are extremely useful for treatment of multiple myeloma.

The entire disclosures of Japanese Patent Application No. 2010-268758 filed on Dec. 1, 2010 and Japanese Patent Application No. 2011-217818 filed on Sep. 30, 2011 including specifications, claims and summaries are incorporated herein by reference in their entireties. 

1. A pyrazole compound of formula (1), a tautomer of the compound, or a pharmaceutically acceptable salt or solvent thereof:

wherein R¹ is a hydrogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl substituted with a halogen atom, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynyl substituted with a halogen atom, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NR¹³, —(R¹²)═NOR¹³, D1 to D23, cyano, phenyl, phenyl substituted with (R¹¹)_(a), benzyl or benzyl having a benzene ring which may be substituted with (R¹¹)_(a), in which when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, and when there are two neighboring R¹¹, the two neighboring R¹¹ may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R¹¹, a 5-membered or 6-membered ring which may have a hydrogen atoms on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R² is a hydrogen atom, a halogen atom, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl substituted with a halogen atom, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynyl substituted with a halogen atom, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NR¹³, —C(R¹²)═NOR¹³, D1 to D23, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R21)_(e), in which when e is an integer of at least 2, each R²¹ may be identical with or different from one another, and when there are two neighboring R²¹, the two neighboring R²¹ may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkenyl optionally substituted with R³¹, C₂-C₆ alkynyl, C₂-C₆ alkynyl optionally substituted with R³¹, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴, benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(g), in which when g is an integer of at least 2, each R¹⁵ may be identical with or different from one another, X is a single bond or —(CR⁶, R⁷)_(n)— R⁴ and R⁵ are each independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R⁴ and R⁵ may form —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂CH₂— to form a 3-membered, 4-membered, 5-membered or 6-membered ring together with the carbon atoms attached to R⁴ and R⁵, R⁶ and R⁷ are each independently a hydrogen atom or C₁-C₆ alkyl, R⁸ is D1 to D23, E1 to E8, M1 to M9, C₃-C₁₀ cycloalkyl, F1, F2, C₃-C₁₀ cycloalkenyl, phenyl or phenyl optionally substituted with (R⁸¹)_(k), in which when k is an integer of at least 2, each R⁸¹ may be identical with or different from one another, and when there are two neighboring R⁸¹, the two neighboring (R⁸¹)_(k) may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—, —OCH₂—O, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R⁸¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, D1 to D23 are aromatic heterocyclic rings of structural formulae, respectively,

E1 to E8 are saturated heterocyclic rings of structural formulae, respectively,

M1 to M9 are partially unsaturated aromatic heterocyclic rings of formulae, respectively,

F1 and F2 are rings of formulae, respectively,

R^(x) is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, —OR⁸², —C(O)R¹², —C(O)OR¹², phenyl, phenyl which may be substituted with (R¹⁵)_(d), benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(d), in which when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another. R^(y) is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, phenyl, phenyl which may be substituted with (R¹⁵)_(d), benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(d), in which when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another, R^(Z) is a halogen atom, cyano, nitro, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, phenoxy, phenyl or phenyl which may be substituted with (R¹⁶)_(m), and when m is an integer of at least 2, each R¹⁶ may be identical with or different from one another, in which when s1, s2 or s3 is an integer of at least 2, each R^(z) may be identical with or different from one another, and when there are two neighboring R^(z), the two neighboring R^(z), may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two neighboring R^(z), a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkoxy, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, nitro, cyano or phenyl, R¹² and R¹³ are each independently a hydrogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ halocycloalkyl, D1 to D23, benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), in which when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, and when there are two neighboring R¹⁴, the two neighboring R¹⁴ may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R¹⁴, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R¹⁴ is a halogen atom, nitro, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, phenoxy or phenyl, R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkyl, C₃-C₆ halocycloalkoxy, nitro, cyano or phenyl, R¹⁶ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkoxy, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkoxy, nitro, cyano or phenyl, and when there are two neighboring R¹⁶, the two neighboring R¹⁶ may form —OCH₂O— to form a 5-membered ring together with the carbon atoms to the two R¹⁶, R¹⁷ is —C(O)OR¹², phenyl or phenyl substituted with (R¹¹)_(a), in which when a is an integer of at least 2, each R¹¹ may be identical with or different from one another, R²¹ is a halogen atom, nitro, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, —OR²³, —C(O)R²⁴, —C(O)OR²⁴, —NR²⁴R²⁵, —C(O)NR²⁴R²⁵, —S(O)₂NR²⁴R²⁵, phenyl or phenyl which may be substituted with (R²²)_(f), in which when f is an integer of at least 2, each R²² may be identical with or different from one other, and when there are two neighboring R²², the two neighboring R^(22's may form —CH) ₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—, —OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—, —CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R²², a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R²² is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkoxy, C₃-C₁₀ halocycloalkyl, C₃-C₁₀ halocycloalkoxy, nitro, cyano or phenyl, R²³ is a hydrogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, phenyl, phenyl which may be substituted with (R²²)_(f), benzyl or benzyl having a benzene ring which may be substituted with (R²²)_(f), in which when f is an integer of at least 2, each R²² may be identical with different from one another, R²⁴ and R²⁵ are each independently a hydrogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ halocycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), 1-phenethyl, 1-phenethyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), 2-phenethyl, 2-phenethyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), in which when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, R³¹ is a halogen atom or phenyl, R³², R³³ and R³⁴ are each independently C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), in which when b is an integer of at least 2, each R¹⁴ may be identical with or different from one another, R⁸¹ is a halogen atom, nitro, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, —OR²³, —C(R⁸³)═NR⁸⁴, —C(R⁸³)═NOR⁸⁴, —C(O)R²⁴, —C(O)OR²⁴, —S(O)cR²⁴, —OS(O)₂R²⁴, —NR²⁴R²⁵, —C(O)NR²⁴R²⁵, —C(S)NH₂, —S(O)₂NR²⁴R²⁵, phenyl or phenyl which may be substituted with (R²²)_(m), in which when m is an integer of at least 2, each R²² may be identical with or different from one another, R⁸² is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy(C₁-C₆) alkyl, phenyl, phenyl which may be substituted with (R¹⁵)_(d), benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(d), in which when d is an integer of at least 2, each R¹⁵ may be identical with or different from one another, R⁸³ and R⁸⁴ are each independently a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl, phenyl which may be substituted with (R¹⁵)_(d), benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(d), in which when d is an integer of at least 2, each R¹⁵′ may be identical with or different from one another, Z is a halogen atom, cyano, nitro, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, —C(O)NH₂, —C(S)NH₂, or —S(O)₂NH₂, a, b, d, e, f, g, k and m are each independently an integer of from 1 to 5, c is an integer of from 0 to 2, q1 is an integer of from 0 to 3, q2 is an integer of from 0 to 5, q3 is an integer of from 0 to 7, q4 is an integer of from 0 to 6, q5 is an integer of from 0 to 4, r is an integer of from 0 to 2, s1 is an integer of from 0 to 4, s2 is an integer of from 0 to 3, s3 is an integer of from 0 to 2, s4 is an integer of 0 or 1, n is an integer of 1, t is an integer of 0 or 1, and u is an integer of 0 or
 1. 2. The pyrazole compound according to claim 1, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is —(CR⁶, R⁷)_(n).
 3. The pyrazole compound according to claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NR¹³, —C(R¹²)═NOR¹³, D1 to D12, D18, D19, D21 to D23, phenyl or phenyl substituted with (R¹¹)a, in which when there are two neighboring R¹¹, the two neighboring R¹¹ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms optionally replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R² is a hydrogen atom, a halogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D1, D2, D4 to D12, D18, D19, D21 to D23, —C(O)R¹², —C(O)OR¹², benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹, the two neighboring R²¹ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴, benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(g), R⁵ are each independently C₁-C₄ alkyl, each of R⁶ and R⁷ is a hydrogen atom, R⁸ is D1, D2, D4, D5, D7 to D12, D19, D22, D23, E1 to E8, F1, F2, C₃-C₁₀ cycloalkyl, phenyl or phenyl optionally substituted with (R⁸¹)_(k), and in which when there are two neighboring R⁸¹, the two neighboring R⁸¹ may form —OCH₂O—, —CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH—, to form, together with the carbon atoms attached to the two R⁸¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R^(x) is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl or phenyl, R^(y) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl or phenyl which may be substituted with (R¹⁵)_(d), R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with (R¹⁶)_(m), R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, nitro or phenyl, R¹² and R¹³ are each independently a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ halocycloalkyl, D2, D4, D5, D7, D21, D22, D23, (R¹⁴)_(b), benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), in which when there are two neighboring R¹⁴, the two neighboring R¹⁴ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹⁴, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R¹⁴ is a halogen atom, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenoxy or phenyl, R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, R¹⁶ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy, and when there are two neighboring R¹⁶, the two neighboring R¹⁶ may form —OCH₂ to form a 5-membered ring together with the carbon atoms to the two R¹⁶, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, nitro, cyano, phenoxy, phenyl or phenyl which may be substituted with (R²²)_(f), R²² is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy and when there are two neighboring R²², the two neighboring R²² may form —OCH₂O—, to form, together with the carbon atoms attached to the two R²², a 5-membered ring, R³², R³³ and R³⁴ are each independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl, phenoxy, nitro or cyano, and Z is a halogen atom or C₁-C₆ alkyl.
 4. The pyrazole compound according to claim 3, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)OR¹², D2, D4, D5, D7, D21, D22, D23, phenyl or phenyl substituted with a (R¹¹), in which when there are two neighboring R¹¹, the two neighboring R¹¹ may form —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹, a 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R² is a hydrogen atom, a halogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D2, D7, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or, phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹, the two neighboring R²¹ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by one or more Z's which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴ (or benzyl, R⁸ is D2, D7, D23, F1, F2, phenyl or phenyl optionally substituted with (R⁸¹)_(k), in which when there are two neighboring R⁸¹, the two neighboring R⁸¹ may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R^(y) is C₁-C₆ alkyl or phenyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with (R¹⁶)_(m), R¹² and R¹³ are each independently a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, R¹⁷ is —C(O)OR¹² or phenyl, R²² is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, R³², R³³ and R³⁴ are each independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl or phenoxy.
 5. The pyrazole compound according to claim 4, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, phenyl or phenyl substituted with (R¹¹)_(a), R² is a hydrogen atom, a halogen atom, C₁-C₆ alkyl, D2, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹, the two neighboring R²¹ may form —OCH₂O—, —OCH₂CH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, R⁸ is D2, F1, F2, phenyl or phenyl optionally substituted with (R⁸¹)_(k), in which when there are two neighboring R⁸¹, the two neighboring R⁸¹ may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹, 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy or phenyl, R¹¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy or nitro, R¹² is C₁-C₆ alkyl, R¹⁷ is —C(O)OR¹² or phenyl, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₁-C₆ haloalkyl, nitro, cyano or phenyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, phenyl or phenoxy.
 6. The pyrazole compound according to claim 1, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R² is a hydrogen atom, a halogen atom, cyano, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₃-C₁₀ cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkenyl substituted with a halogen atom, C₂-C₁₀ alkynyl, C₂-C₁₀ alkynyl substituted with a halogen atom, —C(O)R¹², —C(O)OR¹², —C(R¹²)═NR¹³, —C(R¹²)═NOR¹³, D1 to D23, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹'s, the two neighboring R²¹'s may form —CH₂CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—OCH₂O—, —CH₂CH₂S—, —CH₂SCH₂—CH₂CH₂N(R^(y))—, —CH₂N(R^(y))CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂CH₂OCH₂—, —CH₂OCH₂O—, —OCH₂CH₂O—, —OCH₂CH₂S—, —CH₂CH═CH—, —OCH═CH—, —SCH═CH—, —N(R^(y))CH═CH—, —OCH═N—, —SCH═N—, —N(R^(y))CH═N—, —N(R^(y))N═CH—, —CH═CHCH═CH—, —OCH₂CH═CH—, —N═CHCH═CH—, —N═CHCH═N— or —N═CHN═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, and X is a single bond.
 7. The pyrazole compound according to claim 6, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C₁-C₁₀ alkyl, C₁-C₁₀ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹³)R¹², —C(R¹²)═NOR¹³, D1 to D12, D18, D19, D21 to D23, phenyl or phenyl substituted with (R¹¹)_(a), in which when there are two neighboring R¹¹, the two neighboring R¹¹ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R² is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D1, D2, D4 to D12, D18, D19, D21 to D23, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹, the two neighboring R²¹ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴, benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(g), R⁴ and R⁵ are each independently C₁-C₄ alkyl, R⁸ is D1, D2, D4, D5, D7 to D12, D19, D22, D23, E1 to E9, F1, F2, C₃-C₁₀ cycloalkyl, phenyl or phenyl optionally substituted with (R⁸¹)_(k), in which when there are two neighboring R⁸¹, the two neighboring R⁸¹ may form —OCH₂O—, —CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R^(x) is a hydrogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl or phenyl, R^(y) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl or phenyl which may be substituted with (R¹⁵)_(d), benzyl or benzyl having a benzene ring which may be substituted with (R¹⁵)_(d), R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with (R¹⁶)_(m), R¹¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, nitro or phenyl, R¹² and R¹³ are each independently a hydrogen atom, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₃-C₆ halocycloalkyl, D2, D4, D5, D7, D21, D22, D23, benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), in which when there are two neighboring R¹⁴, the two neighboring R¹⁴ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH—, —CH═CHCH═CH— or —N═CHCH═CH— to form, together with the carbon atoms attached to the two R¹⁴, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R¹⁴ is a halogen atom, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, phenoxy or phenyl, R¹⁵ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy or C₁-C₆ haloalkyl, R¹⁶ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy and when there are two neighboring R¹⁶, the two neighboring R¹⁶ may form —OCH₂O— to form a 5-membered ring together with the carbon atoms to the two R¹⁶, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₁-C₁₀ haloalkyl, C₁-C₁₀ haloalkoxy, nitro, cyano, phenoxy, phenyl or phenyl which may be substituted with (R²²)_(f), R²² is a halogen atom, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkyl or C₁-C₁₀ haloalkoxy and when there are two neighboring R²², the two neighboring R²² may form —OCH₂O— to form, together with the carbon atoms attached to the two R²², a 5-membered ring, R³², R³³ and R³⁴ are each independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl, benzyl having a benzene ring which may optionally be substituted with (R¹⁴)_(b), phenyl or phenyl which may optionally be substituted with (R¹⁴)_(b), R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy(C₁-C₆) alkyl, C₁-C₆ alkoxy(C₁-C₆) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, phenyl, phenoxy, nitro or cyano, and Z is a halogen atom or C₁-C₆ alkyl.
 8. The pyrazole compound according to claim 7, a tautomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —C(O)OR¹², D2, D4, D5, D7, D21, D23, phenyl or substituted with (R¹¹)_(a), in which when there are two neighboring R¹¹, the two neighboring R¹¹ may form —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R¹¹'s, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R² is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, D2, D7, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹, the two neighboring R²¹ may form —OCH₂O—, —OCH₂CH₂O—, —OCH═CH— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₁-C₄ alkoxy(C₁-C₄) alkyl, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)R¹³, —Si(R³²)(R³³)R³⁴ or benzyl, R⁸ is D2, D7, D23, F1, F2, phenyl or phenyl optionally substituted with (R⁸¹)_(k), in which when there are two neighboring R⁸¹, the two neighboring R⁸¹ may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R^(y) is C₁-C₆ alkyl or phenyl, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy, phenyl or phenyl which may be substituted with (R¹⁶)_(m), R¹² and R¹³ are each independently a hydrogen atom, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, R¹⁶ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ loalkyl or C₁-C₆ haloalkoxy, R¹⁷ is —C(O)OR¹² or phenyl, R²² is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy, R³², R³³ and R³⁴ are each independently C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, C₁-C₆ haloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl or phenoxy.
 9. The pyrazole compound according to claim 8, wherein R¹ is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with R¹⁷, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, phenyl or phenyl substituted with (R¹¹)_(a), R² is C₁-C₆ alkyl, D2, benzyl, benzyl having a benzene ring optionally substituted with (R²¹)_(e), phenyl or phenyl optionally substituted with (R²¹)_(e), in which when there are two neighboring R²¹, the two neighboring R²¹ may form —OCH₂O—, —OCH₂CH₂O— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R²¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R³ is a hydrogen atom, R⁸ is D2, F1, F2, phenyl or phenyl optionally substituted with (R⁸¹)_(k), in which when there are two neighboring R⁸¹, the two neighboring R⁸¹ may form —OCH₂O—, —CH₂CH₂CH₂— or —CH═CHCH═CH— to form, together with the carbon atoms attached to the two R⁸¹, a 5-membered or 6-membered ring which may have a hydrogen atom on the ring-constituting carbon atoms replaced by a Z which may be identical with or different from one another, if two or more Z's are present, R^(z) is a halogen atom, C₁-C₆ alkyl, phenoxy or phenyl, R¹¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy or nitro, R¹² is C₁-C₆ alkyl, R¹⁷ is —C(O)OR¹² or phenyl, R²¹ is a halogen atom, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, C₁-C₂ alkoxy(C₁-C₂) alkoxy, C₁-C₆ haloalkyl, nitro, cyano or phenyl, and R⁸¹ is a halogen atom, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy or phenoxy.
 10. A therapeutic agent for multiple myeloma comprising the pyrazole compound according to claim 1, a tautomer of the compound or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. 